• vertebrates;
  • cranial nerves;
  • pharyngeal arches;
  • trigeminal nerve


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The trigeminal, the fifth cranial nerve of vertebrates, represents the rostralmost component of the nerves assigned to pharyngeal arches. It consists of the ophthalmic and maxillomandibular nerves, and in jawed vertebrates, the latter is further divided into two major branches dorsoventrally. Of these, the dorsal one is called the maxillary nerve because it predominantly innervates the upper jaw, as seen in the human anatomy. However, developmentally, the upper jaw is derived not only from the dorsal part of the mandibular arch, but also from the premandibular primordium: the medial nasal prominence rostral to the mandibular arch domain. The latter component forms the premaxillary region of the upper jaw in mammals. Thus, there is an apparent discrepancy between the morphological trigeminal innervation pattern and the developmental derivation of the gnathostome upper jaw. To reconcile this, we compared the embryonic developmental patterns of the trigeminal nerve in a variety of gnathostome species. With the exception of the diapsid species studied, we found that the maxillary nerve issues a branch (nasopalatine nerve in human) that innervates the medial nasal prominence derivatives. Because the trigeminal nerve in cyclostomes also possesses a similar branch, we conclude that the vertebrate maxillomandibular nerve primarily has had a premandibular branch as its dorsal element. The presence of this branch would thus represent the plesiomorphic condition for the gnathostomes, implying its secondary loss within some lineages. The branch for the maxillary process, more appropriately called the palatoquadrate component of the maxillary nerve (V2), represents the apomorphic gnathostome trait that has evolved in association with the acquisition of an upper jaw. J. Morphol. 275:17–38, 2014. © 2013 Wiley Periodicals, Inc.






dorsal ramus


dorsal root ganglia




external nostrils


ciliary ganglion


anterior lateral line ganglion


hyoid arch


lower lip of an ammocoete larva


lateral nasal prominence


mandibular process


mandibular cavity


mandibular mesoderm


Meckel's cartilage


medial nasal prominence




motor root


maxillary process


mandibular arch


nasal epithelium


nasopalatine duct


dentary bone


maxillary bone


premaxillary bone




premandibular cavity


first pharyngeal pouch


second pharyngeal pouch




ramus anguli oris


anterior superior alveolar nerve of V2


ramus alveolaris maxillaris


buccal nerve of lateral line nerve


rami cutanei externi


chorda tympani


frontal nerve


greater palatine nerve


infraorbital nerve of V2


lateral nasal branch of V1


mandibular nerve


medial nasal branch of V1


maxillary nerve


external part of maxillary nerve


nasopalatine nerve of V2


superficial ophthalmic nerve of lateral line nerve


ophthalmic profundal nerve of V1


pharyngeal branch


palatine branch of VII


posterior palatine branch


pretrematic branch


posttrematic branch


ramus temporalis superficialis




sensory root ganglion




upper incisor


upper lip of an ammocoete larva


upper molar


oculomotor nerve


trochlear nerve


root of trigeminal nerve


ophthalmic nerve


maxillary nerve


mandibular nerve


maxillomandibular nerve


facial nerve


acoustic nerve


glossopharyngeal nerve


vagus nerve


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A major component of craniofacial primordia in vertebrates is the cephalic neural crest-derived ectomesenchyme (Le Douarin, 1982; Noden, 1983, 1988; Kuratani, 2012). Specified between the surface ectoderm and the neural plate, the neural crest produces delaminated, migratory cells with pluripotency, being able to differentiate into various cell types (Le Douarin, 1982; Gans and Northcutt, 1983; Noden, 1988). Of the neural crest, the cephalic component is characterized by its skeletogenic and mesenchymal differentiation, not found in the trunk part (Gans and Northcutt, 1983; Shimada et al., 2013). The migrating cephalic neural crest cells predominantly localize to the ventral part of the head, forming three massive ectomesenchymal cell populations. These cell populations are called, from anterior to posterior: the trigeminal crest cells that fill the mandibular arch and more rostral part of the head; hyoid crest cells in the second arch; and circumpharyngeal crest cells filling the postotic pharyngeal arches at the interface between the head and trunk portions of the embryonic body (Kuratani, 1997; Matsuoka et al., 2005). Of these, the trigeminal crest cells are so called because the distribution of these cells largely corresponds to the sensory innervation domains of the trigeminal nerves; this ectomesenchymal region is divided into mandibular and premandibular components (Johnston, 1966; Kuratani and Tanaka, 1990; Kuratani, 1997; Kuratani and Horigome, 2000). This domain is partly covered by the surface ectodermal region of trigeminal placodes. Therefore, the trigeminal ganglionic primordia also differentiate in this neural crest cell stream (Batten, 1957a; Noden, 1988; O'Neill et al., 2007; McCabe and Bronner-Fraser, 2008), similar to other sensory ganglia for branchiomeric nerves (VII–X) that develop both from cephalic crest cells and dorsal/epibranchial placodes in a segmental pattern, as seen in the pharyngeal arches (Fig. 1A). Thus, the peripheral nerve morphology is tightly associated with the craniofacial developmental programs of vertebrates.


Figure 1. Craniofacial development and anatomy of the trigeminal nerve. A: Left: The distribution of the placodes in an early pharyngula embryo of the chicken. Topographical relationships are obvious between the pharyngeal arch and epibranchial placodes. Right: The cranial ganglia and the sensory dorsal root ganglia (drg) at the later embryonic stage. the neuron are from both placode and neural crest. The trigeminal nerve (V) supplies the mandibular arch (MA) as well as the premandibular domain. Most of the facial nerve (VII) supplies the hyoid arch. Redrawn from Le Douarin (1986). B: Schematic drawing of a generalized branchial nerve. Somatosensory components are colored blue, visceral sensory components are green, and special visceral motor fibers are purple. Redrawn from Romer and Parsons (1986). C: Craniofacial primordia of the human embryo. Redrawn from Standring (2004). D: The Dlx code underlying the dorsoventral identity of the pharyngeal arch. The maxillary process (mx) develops as a dorsal growth of the mandibular arch and expresses only Dlx1/2 genes (light blue). Dlx gene expressions are dorsoventrally nested, constituting the Dlx code to specify the arch. Redrawn from Minoux and Rijli (2010). E: Developmental origins of the skeletal elements in the mouse cranium. The maxillary process derivatives are colored light blue and the mandibular process derivatives purple. The rostral components of the upper jaw, such as the premaxillary bone (opmx) and upper incisor (ui), are not mandibular arch derivatives that are patterned through the Dlx code. Redrawn from Depew et al. (2005). F: The anatomy of the trigeminal nerves of the mouse. The maxillary nerve (V) innervates most of the upper jaw and the ventral side of the nasal cavity. Redrawn from Greene (1935). For abbreviations, see the list in the text.

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The trigeminal nerve is the rostralmost component of the branchiomeric nerves, the cranial nerves that innervate the pharynx. It predominantly serves cutaneous sensation in the craniofacial region and innervates the masticatory muscles arising from the first pharyngeal or mandibular arch (Goodrich, 1930; De Beer, 1937; Romer and Parsons, 1986; Standring, 2004; Kardong, 2008). Although the sensory ganglion of the trigeminal nerve appears as a single huge mass of sensory neurons in mammals, this nerve is generally understood to consist of two components: the ophthalmic and maxillomandibular nerves. These have been suggested to represent two successive cranial nerves in a hypothetical ancestor of vertebrates (Goodrich, 1930; De Beer, 1937; Romer and Parsons, 1986; see below). Although no vertebrate species exhibits an entirely separate ophthalmic nerve innervating an extra pharyngeal arch rostral to the mandibular arch, the trigeminal ganglion develops from two separate ganglionic primordia, the ophthalmic ganglion and maxillomandibular ganglion, in many vertebrate species including amniotes (Batten, 1957a,b,c; reviewed by Noden, 1993).

The name of the trigeminal nerve stems from its possession of three major branches. Of these, the ophthalmic nerve (V1) is purely sensory, associated with the ophthalmic ganglion and innervates the preoptic region of the head. This innervation domain does not contain any mandibular arch derivatives but is found rostral to the mandibular arch. In gnathostomes, the maxillomandibular nerve is further divided into two branches: the maxillary (V2) and mandibular (V3) nerves. The motor fibers innervating the mandibular arch muscles are included exclusively in the mandibular nerves, in gnathostomes. On the other hand, the maxillomandibular nerve of the lamprey, a cyclostome, has upper and lower branches, both of which contain motor fibers: these branches are not directly comparable to the V2 and V3 nerves of gnathostomes (see Johnston, 1905b; Song and Boord, 1993; Kuratani et al., 2001; see below).

The trigeminal nerve is classified as one of the branchiomeric nerves. This nerve, or at least its maxillomandibular moiety distributed predominantly in the mandibular arch, has been thought to represent a serial homologue of other members of this category, such as the facial, glossopharyngeal, and vagus nerves. As a general rule, branchiomeric nerves possess two sensory ganglia, the superior and inferior ones, as well as a certain number of branches called the pretrematic and post-trematic branches on both sides of the pharyngeal slit, and the pharyngeal branch that passes longitudinally in the pharyngeal roof (Starck, 1979; Romer and Parsons, 1986; Tanaka, 1987; Fig. 1B). Of those, it is the post-trematic branch that is generally treated as the main branch (Hauptast or Endast) of the branchiomeric nerve, carrying motor fibers to innervate the muscle in the pharyngeal arch, to which the nerve belongs. It is also the longest gustatory nerve innervating the taste buds, thus characterizing the segmental nature of branchiomeric nerves most conspicuously (Johnston, 1905b; Allis, 1920; Goodrich, 1930; Starck, 1979; Romer and Parsons, 1986; Tanaka, 1987; Kuratani and Tanaka, 1990). In this generalization, two major differences are recognized between the trigeminal and the more caudal branchiomeric nerves, highlighting the peculiarity of the trigeminal nerve among the cranial nerves. First, it lacks a long gustatory component innervating taste buds, as seen in the more caudal branchiomeric nerves. Second, the trigeminal ganglion does not develop from a typical epibranchial placode located dorsal to a pharyngeal pouch, as seen in the inferior ganglia of more caudal branchiomeric nerves (Kastschenko, 1887; Batten, 1957a,b,c; D'Amico-Martel and Noden, 1983; Webb and Noden, 1993; Fig. 1A).

The peculiarity of the trigeminal nerve is extended into its topography. As seen in many textbooks, the innervation pattern of the trigeminal nerve branches has been explained by the embryonic composition of the craniofacial primordia (Fig. 1C), just like the other branchiomeric nerves, which develop in a segmental fashion in register with pharyngeal arch segmentation (Goodrich, 1930; Jarvik, 1980; Le Douarin, 1982). In this interpretation, the ophthalmic nerve fibers grow into the medial and lateral nasal prominences and its derivatives (premandibular region; Kuratani, 1990), the maxillary nerve in the maxillary process; and the mandibular nerve in the mandibular process (Kuratani, 1990). Because the jaw has traditionally been regarded as arising from a dorsoventral division of the mandibular arch (Rathke, 1827; Romer and Parsons, 1986; also see Kuratani, 2012), it would thus be reasonable to assume the entire upper jaw to be generally innervated by the maxillary nerve. However, in mammals, recent studies have revealed that the upper jaw is a composite structure derived from both the maxillary process and from the premandibular component. Their rostralmost region, including the incisors that are innervated by the maxillary nerve, is derived from the medial nasal prominence, which is presumed to be innervated by the ophthalmic nerve (Depew et al., 2002; Lee et al., 2004; Ozeki et al., 2004; Minoux and Rijli, 2010; Talbot et al., 2010; Wada et al., 2011; Gillis et al., 2013; Fig. 1D,E). The above concept of jaw development leads to the conclusion that the innervation domain of the maxillomandibular component of the trigeminal nerve does not strictly correspond to the mandibular arch and its derivatives, even if the maxillary nerve is perfectly associated with the upper jaw as described in human anatomy (Standring, 2004; Fig. 1F).

Further insights into the evolution and embryonic morphogenesis of the trigeminal nerve will be fundamental to our understanding of the evolutionary origin of the vertebrate head, the establishment of the oral apparatus and the evolutionary acquisition of the jaw. This study aims at understanding and reconciling the apparent discrepancy between the trigeminal nerve branching patterns, in particular the maxillary nerve, and the developmental composition of the craniofacial primordia with special focus on the innervation pattern of the so-called maxillary nerve in the gnathostomes. Here, we compared embryonic development of the trigeminal nerve in several gnathostome species according to phylogeny, and found that the maxillary nerve in gnathostomes is not primarily associated with the dorsal half of the mandibular arch. Instead, it primarily possesses branches that also innervate the premandibular domain. Together with the morphological pattern of the trigeminal nerve in the cyclostomes, the maxillomandibular nerve must have extended into the premandibular domain in the common ancestor of the gnathostomes.


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Mus musculus (C57BL/6 strain) embryos of 9.5 days postcoitum (dpc), 10.5 dpc, 11.5 dpc, and 12.5 dpc (except for the extraembryonic membranes) were collected according to the developmental stages by Kaufman (1992).


Fertilized eggs of the White Leghorn chicken Gallus gallus were incubated in a humid chamber at 38°C. According to staging by Hamburger and Hamilton (1951; henceforth HH), we collected embryos of HH stages 20, 25, 29, and 35.


Fertilized eggs of the Madagascar ground gecko Paroedura pictus (from the Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan) were incubated in a humid chamber at 38°C and the embryos of 7, 10, 14, and 20 days postoviposition (dpo) were collected according to the developmental stages by Noro et al. (2009).


Fertilized Bester eggs (a commercially established hybrid lineage between Acipenser ruthenus and Huso huso; a gift from Tsukuba Research Institute, Fujikin, Tsukuba, Japan) were kept in the laboratory in fresh water at 16–17°C. We collected stages C, D, E, F embryos, and the larvae of 10 days posthatching according to the staging by Kuratani et al. (2000).


Fertilized eggs of the cloudy catshark Scyliorhinus torazame were obtained from adult animals that were bred at 18°C in seawater tanks. The eggs were transferred to a separate seawater tank, where they were allowed to develop. Embryos were excised from the eggs and we collected stages 25, 27, and 31 embryos according to the developmental stages by Ballard et al. (1993).

All the animal experiments were carried out in accordance with the guidelines of our Institutional Animal Ethics Committee.


To visualize the peripheral nerve in embryos and larvae, we tested several monoclonal antibodies that had been shown to recognize neurons. Of these, antibody 3A10 (Developmental Studies Hybridoma Bank, produced by T. M. Jessell, J. Dodd and S. Brenner-Morton; was the most suitable for this purpose, except for mouse embryos, for which antibody 2H3 (Developmental Studies Hybridoma Bank) was employed. We performed the treatment in the five gnathostome species: mouse (five 9.5 dpc, eighteen 10.5 dpc, and 12 samples each of 11.5 and 12.5 dpc embryos), chicken (10 HH stage 20, 12 HH stage 25, 12 HH stage 29, and six HH stage 35 embryos), gecko (two 7 dpo, three 10 dpo, three 14 dpo, four 20 dpo), sturgeon (14 samples each of stages C and D, 12 samples each of stages E, F and larvae at 10 days post-hatching), and shark (one sample of stage 25 and two samples each of stages 27 and 31). The embryos were fixed with 4% paraformaldehyde in 0.1 mol l−1 phosphate buffered saline, then washed and dehydrated in a graded series of methanol (70, 95%) and stored at 4°C. They were placed in Dent's fixative, a mixture of dimethyl sulfoxide and methanol (1:4), for several days for depigmentation and for blocking endogenous peroxidase activities. One half milliliter of 10% Triton X-100 in distilled water was added and the embryos were further incubated for 30 min at room temperature. After washing in Tris-HCl-buffered saline (TST: 20 mol l−1 Tris-HCl, pH 8.0, 150 mmol l−1 NaCl, 0.01% Triton X-100), the samples were blocked with 5% nonfat dried milk in TST (TSTM). The embryos were incubated in the primary antibody (diluted 1/100 in spin-clarified TSTM containing 0.1% sodium azide) for 2–4 days at room temperature while being gently agitated. The secondary antibody used was horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG (Zymed Laboratories, San Francisco, CA) diluted 1/200 in TSTM, except for mouse embryos, for which HRP-conjugated rabbit anti-mouse IgG1 (Rockland Immunochemicals, Gilbertsville, PA). After a final wash in TST, the embryos were preincubated with the peroxidase substrate 3,3′-diaminobenzidine (DAB: 100 µg/ml) in TS for 1 h. They were allowed to react in TST at the same concentration of DAB with 0.01% (v/v) hydrogen peroxide (35% aqueous solution) for 20–40 min at 4°C. The reaction was stopped and the embryos were placed in 0.5% KOH. The latter treatment successfully cleared the soft tissue of the embryos. The stained embryos were then transferred to a graded series of glycerol/water solutions and stored in 60% glycerol in water for observation.


The sturgeon embryos (six samples of stage C and four samples each of stages D and E) were fixed in Serra's fixative, dehydrated and embedded in paraffin wax. Sections were cut at a thickness of 6 µm. To visualize the nerve axons, we conducted immunohistochemistry. The primary antibody was CD57 (HNK-1, Becton, Dickinson), and the secondary antibody was HRP-conjugated goat anti-mouse IgM (Zymed Laboratories, San Francisco, CA). Then the sections were stained with hematoxylin and eosin, according to standard protocols.


Illustrations were prepared by photographing specimens and tracing the outlines of the nerves and craniofacial primordia onto tracing paper (Tochiman No. 955T; Tochiman, Tokyo, Japan). These were scanned using a Fuji-Xerox DocuCentre IV C6680 (Fuji Xerox, Tokyo, Japan).

For three-dimensional (3D) reconstruction, the stained sections of embryos were digitized using an Olympus BX60 microscope equipped with an Olympus DP70 camera and the Olympus DP controller software (Olympus, Tokyo, Japan). On the digitized sections, each embryonic component was identified and reconstructed using the Avizo 3D Visualization Framework (Maxnet, Tokyo, Japan).

Whole-Mount In Situ Hybridization

At least 10 mouse embryos each of stages 10.5, 11.5, and 12.5 dpc are prepared for whole-mount in situ hybridization. DIG-labeled antisense RNA probes were synthesized according to the manufacturer's instructions (Roche Applied Science, Tokyo, Japan and Thermo Fisher Scientific, Yokohama, Japan) and whole-mount in situ hybridization was performed according to the methods of O'Neill et al. (2007). After color reactions were complete, the embryos were postfixed in 4% paraformaldehyde/PBS and photographed using a Leica MZ16FA microscope equipped with a Leica DFC300 camera and the LAS imaging software (Leica, Tokyo, Japan).


For the terminology of nerves, Greene (1935) was consulted for the mouse, and Watanabe and Yasuda (1970) for the chicken and gecko. Herein, we use the term “the palatine branch of the facial nerve” for those nerves that arise from the geniculate ganglion and pass rostrally to innervate the pharyngeal roof and palate.


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Mouse (Mus musculus)

In the mouse embryo at 9.5 days postcoitum (dpc), the mandibular arch was clearly visible as the rostralmost craniofacial component (Fig. 2A), in which maxillary and mandibular processes become discernible by 10.5 dpc (Fig. 2B,B′). The Dlx1-negative domain rostral and medial to the maxillary process could be regarded as the premandibular domain (Fig. 3A,A′). In a 10.5 dpc embryo, medial and lateral nasal prominences were also visible on both sides of the external nostrils (Fig. 2B,B′). At this stage, a single trigeminal ganglionic primordium had already grown three branches: the ophthalmic profundal nerve (ropht) grew rostrally from the ganglion, passing dorsal to the eye toward the premandibular domain; the maxillary nerve (rmx) and the mandibular nerve (rmd) were found in the maxillary and mandibular processes, respectively (Fig. 2B). In the palatal view, the palatine branch of VII (rplt) was also observed (Fig. 2B′).


Figure 2. Development of the trigeminal nerve in the mouse embryo. A: Left lateral view of an embryo at 9.5 days postcoitum (dpc). Three branches of the trigeminal nerve have just appeared. B: 10.5 dpc embryo. The maxillary process (mx) and the mandibular process (md) are clearly defined. B′: Palatal view of a 10.5 dpc embryo. The palatine branch of cranial nerve VII (rplt) supplies the midline of the palate. C: Left lateral view of an 11.5 dpc embryo. The infraorbital nerve (rio) supplies the lateral surface of the maxillary process. This nerve innervates the sinus hair and upper lip. C′: Enlarged view of the box in C after the infraorbital nerve has been removed. The nasopalatine nerve (rnpl) has split medially from the proximal part of the maxillary nerve. C″: A palatal view of the 11.5 dpc embryo. The small nasopalatine nerve (rnpl) issues from the proximal part of the maxillary nerve. The nasopalatine nerve makes an anastomosis with the palatine branch of VII (rplt). D: 12.5 dpc embryo, left lateral view. D′: Magnified view of the box in D. The greater palatine nerve (rgp) is growing from the anastomosis between the nasopalatine nerve and the palatine branch of VII. D″: 12.5 dpc, palatal view. The nasopalatine nerve (rnpl) passes between the pair of nasopalatine ducts (npld) to supply the primary palate. The greater palatine nerve (rgp) supplies the primordia of the secondary palate. The small branch splitting from the infraorbital nerve is the superior alveolar nerve. The rest of the infraorbital nerve supplies sinus hair primordia. For abbreviations, see the list in the text.

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Figure 3. Expression patterns of Dlx1 in the mouse upper jaw. A–C: The expression of Dlx1 from 10.5 dpo to 12.5 dpo. D–F: Immunostained cranial nerves in embryos of equivalent stages. A: Dlx1 is expressed strongly in the maxillary process (mx). B: In 11.5 dpc embryos, Dlx1 expression is also found in the medial nasal prominence but not in the primary palate. E: Embryo at 11.5 dpc, similar to the stage shown in figure 2C″. Most of the maxillary nerve resides in the domain that expresses Dlx1 clearly. On the other hand, the nasopalatine nerve (rnpl) supplies the primary palate where Dlx1 is not expressed. For abbreviations, see the list in the text. Scale bar = 500 µm.

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By 11.5 dpc, the rostral part of the maxillary nerve had also ramified into a number of fine caliber branches, of which the lateralmost supplied the epidermis, representing an early developmental state of the infraorbital nerve (rio) that will innervate the sinus hair of the upper lip later in development (Fig. 2C). Another set of branches split medially from the proximal part of the maxillary nerve. Some of these communicated with the palatine branch of VII and grew further rostrally and medially toward the rostrum (Fig. 2C,C′).

At the same stage, the rostral end of the maxillary process had fused with the posterior portions of the lateral and medial nasal prominences (Fig. 2C′). The lateral part of the maxillary process had covered the upper jaw to form the upper lip, in which numerous fine nerves originating from the infraorbital nerve were distributed (Fig. 2C′). Medial to this nerve, the superior alveolar nerve was growing rostrally in the maxillary process (Fig. 2C′). In later development, this nerve innervated the upper incisors from the labial side (Fig. 2D′). Even more medially, there was another nerve that had made its first appearance by 11.5 dpc to innervate the primary palate (Fig. 2C′,C′′,D′,D′′). Comparing its position with the expression pattern of Dlx1, it became clear that the nerve grew beyond the medial limit of the maxillary process that expressed the gene, showing that this nerve extended peripherally into the premandibular domain (Fig. 3B,B′,E). The longitudinal pathway of this nerve was found adjacent to the nasal septum and we identified it as the nasopalatine nerve of V2 (rnpl), based on its morphology, its possession of the pterygopalatine ganglion, and its anastomosis with the palatine branch of VII (rplt). The nasopalatine nerve in humans is known as one of the major components of V2, supplying the ventral part of the nasal septum and incisors as well as the anterior soft palate on the upper jaw (Bohn, 1961; Standring, 2004). It is primarily composed of sensory fibers innervating the mucosa, but also contains some postganglionic parasympathetic fibers (Standring, 2004). On the other hand, the dorsal part of the nasal septum and lateral wall of the nasal sac were supplied by the medial and lateral nasal branches of V1 (rmn and rln; Fig. 2D; Standring, 2004).

At least in the mouse, the maxillary nerve, unlike the role its name implies, innervates structures derived from the premandibular ectomesenchyme, if they still represent parts of the upper jaw in a functional sense. The incisors, which are derived from the medial nasal prominence, are known to be innervated by both the superior alveolar and nasopalatine nerves. Interestingly, in the cleft palate mutant of human embryos, whose medial nasal prominence and the maxillary process fail to fuse, the incisors are still innervated by the nasopalatine nerve despite lacking the innervation by the superior alveolar nerve (Bohn, 1963). This supports the idea that the nasopalatine nerve primarily supplies the medial nasal prominence. By contrast, the latter nerve has been secondarily established in mammals, in which the maxillary process-derived upper lip covers most of the medial nasal prominence. Therefore, in mammals, the maxillary nerve has at least two developmental components as its targets: the maxillary process derivatives where most of the fibers are distributed and the premandibular (medial nasal prominence-derived) domain that receives the nasopalatine nerve. To confirm whether this situation is shared with other amniotes, we investigated the case of the chicken and lizard.

Chicken (Gallus gallus)

In the chicken embryo, overt maxillary and mandibular processes began to be discernible at HH stage 20 (Fig. 4A) when the trigeminal ganglionic primordia consisted of two separate components: the ophthalmic and maxillomandibular ganglionic primordia (Fig. 4A). Similar to the pattern found in the 9.5 dpc mouse embryo, the ophthalmic profundal nerve anlage grew rostrally passing dorsal to the eye, and the major part of the maxillomandibular nerve anlage was found in the domain of the mandibular arch (Fig. 4A).


Figure 4. Development of the trigeminal nerve in the chicken embryo. A: Left lateral view of a HH stage 20 embryo. The ophthalmic and maxillomandibular ganglia have appeared clearly. The maxillary nerve has not appeared yet. B: HH stage 25 embryo. From the ophthalmic profundal nerve, the medial nasal nerve (rmn) and lateral nasal nerve (rln) have grown toward the medial nasal prominence (mnp) and lateral nasal prominence (lnp), respectively. The maxillary nerve (rmx) innervation domain corresponds to the maxillary process and the palatine branch of cranial nerve VII (rplt) supplies the primary palate. B′: Palatal view of a HH stage 25 embryo. C: Left lateral view of an HH stage 29 embryo. The peripheral part of the oculomotor nerve (III), the eyeball and the lower jaw have been removed. C′: HH stage 29, palatal view. D: Left lateral view of an HH stage 35 embryo. The eyeball and the lower jaw have been removed. D′: HH 35 stage embryo, palatal view.

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By HH stage 25, medial and lateral nasal prominences had developed in the premandibular domain (similar to the 10.5 dpc mouse embryo). When compared with the mouse embryos, growth of the ophthalmic nerve bundles was faster, and the medial and lateral nasal branches (rmn and rln) were already found in the rostral end of this nerve and into the mandibular arch; the maxillary and mandibular nerves (rmx and rmd) had already begun to grow (Fig. 4B,B′). In the palate, the palatine branch of VII was growing rostrally (Fig. 4B′).

The primordium of the upper jaw had clearly been established by HH stage 29, when the maxillary process and the medial nasal prominence fused with each other. Unlike in the mouse (Figs. 1C and 2D,D′), it was the medial nasal branch of V1 that innervated the rostralmost part of the upper jaw morphologically (Fig. 4C,C′). On the other hand, the maxillary nerve had bifurcated into several branches distally, of which the most medial corresponded to the alveolares maxillaris (rax). The latter nerve, similar to the nasopalatine nerve in the mouse, communicated with the palatine branch of VII. However, this nerve in the chicken embryo passed lateral to the nasopalatine duct (npld), unlike the mammalian nasopalatine nerve that passes medial to the duct. Apparently, there was no counterpart of the mammalian nasopalatine nerve in the chicken embryo and the primary palate and ventromedial part of the medial nasal prominence were supplied by the palatine branch of VII. The ramus anguli oris (rao) arose from the proximal part of the mandibular nerve and also communicated with the palatine nerve. However, the ramus anguli oris supplied a region posterior to the secondary palate, resembling more the greater palatine nerve (rgp) in mammals.

From the above results, the chicken and mammalian embryos were similar to each other in terms of craniofacial primordial composition, as were their peripheral nerve distribution patterns. However, there was a striking difference in the innervation pattern in the maxillary and premandibular domains. In particular, the nasopalatine nerve appears to be absent in the avian embryo, so the rostral part of the upper jaw was supplied by different cranial nerves between the two species. As a step to understanding the evolutionary sequence of upper jaw/palate/rostrum innervation patterns, we next observed another amniote, gecko embryos.

Madagascar Ground Gecko (Paroedura pictus)

Geckos belong to the lizards and share a common diapsid ancestor with birds. They possess teeth and have retained some other traits that have been lost among avians. However, we found the craniofacial anlagen and developmental patterns of trigeminal nerves to be very similar between the gecko and chicken.

Both maxillary and mandibular processes were seen in an embryo of P. pictus 7 days postoviposition (dpo; Fig. 5A). Compared with the chicken embryo, the development of the trigeminal nerve anlage was slightly accelerated and the maxillary and mandibular nerves were already visible at this stage (Fig. 5A). In the 10 dpo embryo, although the medial and lateral nasal prominences were not yet visible, the ophthalmic profundal nerve had already reached the rostral tip of the premandibular domain and the palatine branch of VII (rplt) had innervated the palate (Fig. 5B).


Figure 5. Development of the trigeminal nerve in the gecko embryo. A: Left lateral view of an embryo at 7 days postoviposition (dpo). Although the morphology of the craniofacial primordia is similar to that of the HH stage 20 chicken embryo (Fig. 4A), the maxillary nerve (rmx) appears at an earlier stage. B: Left lateral view of a 10 dpo embryo. The palatine branch of cranial nerve VII (rplt) supplies the primary palate. C: Left lateral view of a 14 dpo embryo. The medial nasal nerve (rmn) and lateral nasal nerve (rln) supply the medial nasal prominence (mnp) and lateral nasal prominence (lnp), respectively. The trigeminal branching patterns at this stage are similar to that in a chicken embryo at HH stage 25 (Fig. 4B). However, in the gecko, the supratemporal nerve (rtem) grows from the ophthalmic ganglion (V1), whereas an equivalent nerve in the chicken grows from the maxillomandibular ganglion (V23). C′: Palatal view of a 14 dpo embryo. Similar to chicken embryos, communications are found between the maxillary nerve and the palatine branch of cranial nerve VII in the rostral part of the upper jaw. D: Embryo at 20 dpo, left lateral view. The peripheral rami of the oculomotor nerve (III) and the eyeball have been removed. D′: Palatal view of a 20 dpo embryo. For abbreviations, see the list in the text.

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The medial and lateral nasal prominences became visible at 14 dpo, both of which had received nerve fibers from the ophthalmic profundal nerve (rmn and rln; Fig. 6C). Of these nerves, the medial nasal branch (rmn) innervated the rostral tip of the upper jaw, as seen in the chicken embryo (Fig. 5C′: compare with Fig. 4B′). The maxillary process had made contact with the medial nasal prominence by this stage. By 20 dpo, the lepidosaurian feature had become apparent in that the rostral tip of the upper jaw was still innervated by the medial nasal branch (Fig. 5D,D′). The secondary palate was innervated by the posterior palatine nerve arising from the anastomosis between the palatine nerve and the proximal part of the maxillary nerve. It passed along a course different from ramus anguli oris in the chicken embryo, in which the nerve arose from the mandibular nerve. The palatine branch of VII (rplt) had established communications with the maxillary nerve by means of several fine branches (Fig. 5C′,D′). Thus, most patterns of craniofacial innervations resembled each other among the chicken and gecko embryos, and neither of them possessed homologues of the nasopalatine nerve as observed in mammals. It is likely that the absence of the latter represents a diapsid-specific condition. Differences between the gecko and chicken embryos were limited to the origin of the superficial temporal nerve, which arose from the ophthalmic nerve in the former and from the maxillomandibular nerve in the latter (Fig. 5B–D). Notably, the primary palates in diapsids are innervated by a branch of the facial nerve (Haller and Hallerstein, 1934; Watanabe and Yasuda, 1970), either as a diapsid-specific trait, or a general pattern for amniotes, among which only mammals have secondarily acquired the nasopalatine branch of the maxillary nerve. To determine the evolutionary polarity of the absence/presence of the nasopalatine nerve, we next observed anamniotic vertebrates.


Figure 6. Development of the trigeminal nerve in the Bester. The lateral line nerves are removed from B–D′. A: Stage C embryo, left lateral view. There are anterior and posterior divisions in the maxillomandibular nerve; the anterior division is marked by a single asterisk. B: stage D, left lateral view. A new branch has appeared from the proximal part of the mandibular nerve (double asterisks). B′: Stage D embryo, palatal view. C: Stage E embryo, left lateral view. The palatoquadrate (pq) is found at the same dorsoventral level as the branch marked with a double asterisk. C′: Stage E embryo, palatal view. D: Larva at 10 days of age, left lateral view. D′: Larva at 10 days of age, palatal view. For abbreviations, see the list in the text.

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Sturgeons belong to the ray-finned fishes and have a specialized type of jaw suspension: the oral skeleton consists only of the palatoquadrate and Meckel's cartilages, which are both separated from the neurocranium (De Beer, 1937; Marinelli and Strenger, 1973). Therefore, unlike other gnathostomes their upper jaw is composed exclusively of maxillary process derivatives. We chose the Bester, a commercially established hybrid between Acipenser ruthenus and Huso huso, as an additional species to investigate further the developmental patterning of the trigeminal nerve morphology.

By stage C, corresponding to the early pharyngula, the Bester embryo had developed several pharyngeal arches, but the morphological extent of the mandibular arch remained obscure, with no overt maxillary or mandibular processes seen on external embryonic morphology. Nevertheless, the embryos already had developed a primordial maxillomandibular ganglion that had grown two branches anteroposteriorly, resembling the maxillary and mandibular nerves in other gnathostomes (Sewertzoff, 1928; Fig. 6A). At stages D and E, the anterior nerve of V23 (marked by a single asterisk in Fig. 6) did not innervate the upper jaw (the domain of the palatoquadrate) except for a minor number of fine fibers; the major component of this nerve innervates the rostrum of the head, containing the nasal sac and barbels (Sewertzoff, 1928; Fig. 6). The branch arising from this nerve, referred to as the mandibular nerve by Sewertzoff (1928; marked by double asterisks in Fig. 6B–D′), actually innervated the upper jaw. Therefore, the anterior nerve appeared to innervate the premandibular domain primarily, which was further ascertained by reconstruction of embryos at stages C, D, and E (Fig. 7). At stage C, premandibular and mandibular cavities were present in the rostral mesoderm and the mandibular arch could be identified as a domain containing a mesodermal core that grew ventrally from the mandibular cavity (Fig. 7B-B″,C). Such a mesodermal configuration has also been reported in elasmobranch embryos (Marshall, 1881; van Wijhe, 1882; Adachi and Kuratani, 2012). At stage D, the palatoquadrate and Meckel's cartilages were found below the level of the branching point of the anterior nerve (Fig. 7D), again implying that the major part of this nerve is located in the premandibular domain. As found at stage E, this nerve resembled the mammalian nasopalatine nerve in terms of its innervation domain as well as communication made between this nerve and the palatine branch of VII (Fig. 6D,D′). Similar nasopalatine-like branches have also been reported in Amia calva (Allis, 1897; Norris, 1925) and Polypterus (Allis, 1922; Piotrowski and Northcutt, 1996).


Figure 7. Three-dimensional (3D) reconstructions of the head of the Bester embryo. A: Dorsal view of a stage C embryo. B–B″: Sagittal sections stained immunochemically with an anti-HNK-1 antibody. C,C′: 3D reconstructed image of a stage C embryo, based on the same specimen as shown in B–B″. Peripheral nerves have been removed in C. The mandibular mesoderm (mdm; pink) is distributed ventral to the mandibular cavity (mdc; red). The domain surrounding the mandibular mesoderm rostral to the first pharyngeal pouch (pp1) can be defined as the mandibular arch. The trigeminal nerve (V: yellow) and the facial nerve (VII: green) have been added in C′. D: Stage D embryo. The palatoquadrate (pq) appears as the upper jaw skeleton, in which a small branch from the maxillomandibular nerve is distributed (double asterisks) The larger anterior division of the maxillomandibular nerve (single asterisk) supplies the snout and barbels. E: Stage E embryo. Trabecular cartilage has appeared medial to the maxillomandibular nerve branch marked with a single asterisk.

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As in the sturgeon, in sharks and rays the skeletal elements of the oral apparatus are formed solely from the mandibular arch. This condition has also been regarded as a derived feature within the elasmobranch lineage (Maisey, 2008; Brazeau, 2009).

In a stage 25 embryo of S. torazame, an overt and undifferentiated mandibular arch was observed and ectomesenchymal expression of Dlx1,2 has been demonstrated in this arch (Compagnucci et al., 2013; Gillis et al., 2013). Thus, the mandibular/premandibular boundary can be inferred by this gene expression pattern (see Kuratani et al., 2012). At this stage, the trigeminal ganglion anlage had not reached the developmental state to grow a nerve branch anlage (Fig. 8A). By stage 27, the dorsal part of the mandibular arch had begun to grow rostrally to form the maxillary process (Fig. 8B,B′). The ventral part, on the other hand, could be seen as the mandibular process. Rostrally, although the nasal pit was clearly observable, medial and lateral nasal prominences were not conspicuous (Fig. 8B′). By this stage, both the maxillary and mandibular nerves could be seen to innervate the maxillary and mandibular processes, respectively (Fig. 8).


Figure 8. Development of the trigeminal nerve in the shark embryo. A: Stage 25 embryo, left lateral view. B: Stage 27 embryo, left lateral view; the lateral line nerves have been removed. B′: A palatal view of a stage 27 embryo. C: Stage 31 embryo, left lateral view; the lateral line nerves have been removed. C′: A palatal view of a stage 31 embryo; the lateral line nerves and the left part of the lower jaw have been removed. For abbreviations, see the list in the text.

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By stage 31, maxillary and mandibular processes on both sides had fused with their counterparts to complete the oral apparatus (mandibular arch-derived jaw; Fig. 8C,C′). At this stage, the maxillary nerve consisted of two parts. The posterior or major part of it innervated the margin of the upper jaw, whereas the anterior part further extended rostrally into the premandibular domain, passing medial to the nasal capsules. Morphologically, therefore, this nerve resembles the nasopalatine nerve of mammalians.

The morphological pattern of the shark trigeminal nerve resembled that of the sturgeon in that the maxillary nerve possessed a branch that innervates the premandibular domain with almost no fibers distributed in the upper jaw. However, the distribution of the palatine branch of VII differed substantially between the two: that of S. torazame grew rostrally along the ventral aspect of the palatoquadrate to innervate the rostral oral roof near the rostral end of the palatoquadrate. Thus, this nerve never extended more rostrally than in sturgeons and diapsids, in which counterparts of this nerve further innervated the snout and ventromedial aspect of the nasal capsule (Fig. 8B′,C′) and it did not establish communication with trigeminal nerve branches in the shark.


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  9. Supporting Information

In the present study, we described the developing trigeminal nerves in the embryos of a variety of gnathostome species, namely, M. musculus, G. gallus, P. pictus, the Bester, and S. torazame, to understand evolutionary changes in the peripheral morphological patterns of this nerve, especially in their relationships to craniofacial development. Simultaneously, we rationalized the nomenclature of the trigeminal nerve branches, in particular those arising from the maxillomandibular component of the nerve. As a result, we came to realize that the branch of the maxillary nerve called the nasopalatine nerve potentially represents a highly enigmatic component of the maxillary nerve, and is a key to understanding the craniofacial evolution of vertebrates.

Comparative and experimental embryologists have long recognized the parallel relationships between the morphology of the peripheral nerves and mesenchymal composition in developing embryos (Kuratani, 1990, 1997; Kuratani and Tanaka, 1990; Kuratani and Kirby, 1991, 1992; Kuratani et al., 1997; Kuratani and Eichele, 1993; Noden, 1993; Schlosser and Roth, 1997a,b). Thus, the peripheral morphology of the nerves reflects the body plan of embryos. As for the segmental pattern of the spinal nerves, which is widespread among vertebrates (Goodrich, 1930; Ota and Kuratani, 2008), segmentation of the mesoderm has primary roles in patterning the peripheral axonogenesis. Namely, the growth patterns of motor fibers as well as the distribution of dorsal root ganglion-forming crest cells depend on the presence of somites (Detwiler, 1934; Keynes and Stern, 1984; Tosney, 1988). As for the morphology of the branchiomeric nerves, nerve root formation and neuronal specification have been shown to be prefigured by the selective adhesion of the neural crest cell populations, especially onto the even-numbered rhombomeres of the hindbrain (Moody and Heaton, 1983a,b,c; Kuratani and Eichele, 1993), and not by the pattern of paraxial mesoderm. More peripherally, inferior ganglia arise from the epibranchial placodes that are induced by endodermal pharyngeal pouches (Begbie et al., 1999). Therefore, for the peripheral morphology of the branchiomeric nerve, pharyngeal pouch segmentation imposes the development of serially homologous patterns among the branchiomeric nerves; in that respect, the trigeminal nerve appears rather exceptional.

The traditional view of comparative morphologists assigned the ophthalmic nerve to the hypothetical ancestral pharyngeal arch once believed to have been present in front of the mandibular arch (premandibular arch). That concept was highly influenced by the idea of head segmentation. Whether the paraxial mesoderm in the head contains segmented blocks of compartments serially homologous with somites in the trunk, it was almost unanimously accepted that the pharyngeal arches are serially homologous among themselves, each of which is accompanied by branchiomeric cranial nerves (V1, V23, VII, IX and X; Gegenbaur, 1872; Balfour, 1878; Marshall, 1881; van Wijhe, 1882; Goodrich, 1930; De Beer, 1937). Based on the dual nature of the trigeminal nerve, the existence of one or more premandibular “arches” was assumed by some morphologists, and prespiracular gill slits were sought in structures such as eyes, mouth, and nostrils (Goodrich, 1930; Sewertzoff, 1931; De Beer, 1937; reviewed by Bjerring, 1977; Jarvik, 1980; and by Kuratani et al., 1997). It is true that the premandibular domain of the vertebrate head contains extensive neural crest-derived ectomesenchyme that develops into cartilages resembling pharyngeal arch skeletal elements (trabecula cranii: Huxley, 1874; Couly et al., 1993; Wada et al., 2011; Kuratani, 2012). Nevertheless, it lacks some fundamental embryonic structures that define pharyngeal arches such as a pharyngeal endodermal pouch, pharyngeal arch muscles and their primordia (see Kastschenko, 1887; Graham et al., 2005). In both extant and fossil cyclostomes, no evidence was found for the presence of any muscularized pharyngeal arches in front of the mandibular arch (Janvier, 1996; see Johnels, 1948 and Kuratani et al., 2004 for the nature of the lamprey trabecula). Absence of Dlx transcripts in the premandibular ectomesenchyme also emphasizes the different developmental pattern of this ectomesenchyme from the rest of the cephalic ectomesenchyme that resides in the pharyngeal arch (see below). Based on developmental and recent comparative morphological evidence, we will not discuss the morphology of the trigeminal nerve in the context of head segmentation in the present paper. Rather than regarding the ophthalmic nerve as a degenerated branchiomeric nerve and its innervation domain as a highly modified pharyngeal arch, hereafter we will simply call this domain filled with the Dlx-negative ectomesenchyme the premandibular “region” or “domain.”

Morphology of the Trigeminal Nerve

Contrary to the general understanding among developmental biologists, the innervation domain of the so-called maxillary nerve does not coincide with the pattern of upper jaw development. It is probably the most curious problem associated with the morphology of the gnathostome trigeminal nerve. Namely, the upper jaw in jawed vertebrates is generally composed of at least two different primordia: the maxillary process derived from the mandibular arch, and derivatives of a more rostrally located primordium, the medial nasal prominence. The latter represents a premandibular structure, found rostral to the mandibular arch (Lee et al., 2004; Standring, 2004; Wada et al., 2011). Thus, the neural crest's contribution and apparent morphological innervation pattern in the upper jaw do not correspond to each other in terms of crest cell contribution and embryonic composition of the craniofacial region. In mammals, the rostral part of the upper jaw, containing the premaxillary bone and incisors, is innervated by a single component of the trigeminal nerve: the maxillary nerve (Fig. 1F). Exceptions are encountered in the elasmobranchs and sturgeons, where the upper jaw skeleton is solely formed from the palatoquadrate. This suggests that their upper jaw is purely of mandibular arch origin (Figs. 7D,E and 8C,C′). Nevertheless, the situation of the upper jaw skeleton such as these examples appears to represent a derived condition, because more basal lineages of chondrichthyes, a single ethmoidal internasal septum exists in the anterior midline and it separates palatoquadrates left and right, as found in the fossil records. Moreover, the mesial part of the upper tooth row is on the ethmoidal internasal septum in some animals (e.g., Doliodus), that condition is considered to be plesiomorphic for chondrichthyes (Brazeau, 2009; Maisey et al., 2009; Khonsari et al., 2013). Thus, the above noted inconsistency regarding the maxillary nerve appears to hold generally true for living gnathostomes (as for jawless vertebrates; see below).

The dual origin of the gnathostome upper jaw in a functional sense (the tooth-bearing region of the upper jaw) was inferred from several labeling experiments (Shigetani et al., 2000; Cerny et al., 2004; Lee et al., 2004; Wada et al., 2011). Labeling the mandibular arch ectomesenchyme resulted in the distribution of the labeled cells only in the posterior part of the upper jaw as a functional unit, corresponding to the domain of the palatoquadrate: the dorsal half of the mandibular arch skeleton (Goodrich, 1930; De Beer, 1937). The more rostral moiety of the upper jaw is derived from the premandibular part of the trigeminal crest cells, especially those called the preoptic crest cells that localize in the lateral and medial nasal prominences (Johnston, 1966; Osumi-Yamashita et al., 1997; Wada et al., 2011). Thus, most probably, the enigmatic nature of the trigeminal nerve is to be ascribed to an atypical pattern of embryonic environment where the nerve develops, and especially to the fact that the mandibular arch represents one of the most functionally specialized pharyngeal arches in the differentiation of the oral apparatus. In the following discussion, we will focus on the comparative morphology and development of the maxillary nerve in gnathostomes. To understand better the evolution of the mandibular arch-related and premandibular domains in vertebrates, we also discuss the cyclostome embryonic patterns to explore further the evolutionary origin of the gnathostome jaws.

Composition of the Upper Jaw

Understanding the morphology of the trigeminal nerve is relevant to understanding the development and evolution of the mandibular arch and its derivative, the jaw. Several genetic experiments support the dual origin of the upper jaw as presented above. For example, homeobox-containing Dlx genes are upregulated in the pharyngeal arch ectomesenchyme of vertebrate embryos and, especially in the gnathostomes, the Dlx gene members are expressed in a nested fashion along the dorsoventral axis of the arches. Dlx1 and Dlx2 are expressed in the entire pharyngeal ectoderm, Dlx5 and Dlx6 in the ventral half of the arches (including the dorsoventral hinge regions) and Dlx3 and Dlx7 in the ventralmost domain of the arches (Depew et al., 2002, 2005; Fig. 1D). This pattern of Dlx family expressions, generally known as the Dlx code, is understood to underlie the dorsoventral specification of the gnathostome pharyngeal arches (Gillis et al., 2013). In the mouse, double knockout of Dlx5 and Dlx6, the genes specifying the ventral moiety of the mandibular arch, results in transformation of the identity of the lower jaw into that of the upper jaw (Depew et al., 2002). In contrast, gain-of-function experiments affecting the same genes lead to the duplication of the upper jaw identity in the upper jaw domain (Depew et al., 2005; Sato et al., 2008). Curiously, the upper jaw region of the latter mutant possesses two pairs of incisors, one pair arising from the rostral tip of the duplicated dentary and the other on the endogenous premaxillary bone. Thus, the rostral domain of the upper jaw is independent of the Dlx code, as is expected from the expression pattern of the Dlx genes and only the posterior part of the upper jaw was transformed into the entire lower jaw as the mandibular arch derivative in the double knockout mutant mouse (Sato et al., 2008).

Given the dual origin of the gnathostome upper jaw, its rostral part should be innervated by the branches of ophthalmic nerves, not by those of the maxillomandibular. That pattern corresponds exactly to our findings in the two diapsid species, G. gallus and P. pictus (Haller and Hallerstein, 1934; Watanabe and Yasuda, 1970; Figs. 4 and 5). Clearly, this prediction will only be justified if the maxillomandibular innervation is restricted to the mandibular arch derivatives. However, it is also true that the other branchiomeric nerves do not follow such a rigid pattern as typically seen in the pretrematic nerves (Alcock, 1898; Johnston, 1905a; Kuratani et al., 1997). Even the chorda tympani, which tends to be regarded as the post-trematic, major branch of the facial nerve, takes a pretrematic course in some diapsids (Kuratani et al., 1988 and references therein). In the maxillary nerve as well, many gnathostomes develop a branch, the nasopalatine nerve, that grows beyond the limit of the maxillary process recognized by its Dlx transcripts, and extends into the premaxillary bone and nasal regions (Fig. 2C′, D′). This branch is universally seen in mammals (Greene, 1935; Standring, 2004), but not in diapsids (Haller and Hallerstein, 1934; Watanabe and Yasuda, 1970).

It appears that the condition in diapsids accords well with the hitherto expected relationship between innervation patterns and developmental primordia, namely, the maxillomandibular nerves for the mandibular arch derivatives, and the ophthalmic nerve for the premandibular domain (Figs. 4 and 5). This makes the mammalian configuration somewhat exceptional, and it was apparently acquired as an autapomorphy. By observing basal lineages of gnathostomes, we performed an out-group comparison to determine the nature of the premaxillary innervation (see below).

The Nasopalatine Nerve in Gnathostomes

In the present study, we found that the nasopalatine nerve (V2) does not exist in nonmammalian amniotes (Figs. 4 and 5). This situation raises two possibilities: either the nerve is generally absent in amniotes and only mammals have acquired it; or it was lost in the lineage leading toward diapsids. However, data on out-groups are rather poor for determining the evolutionary origin of this nerve. For example, various patterns exist for the trigeminal nerve's pathway in amphibians. In the axolotl, Ambystoma mexicanum (Supporting Information Fig. S1), development of the maxillary nerve is relatively later and smaller than other branches of the trigeminal nerve. It was seen initially as fine fibers along the infraorbital lateral line nerve and possessed no branches that innervated the primary palate. Instead, the ophthalmic nerve was well developed, issuing a branch that innervated the rostral end of the palate. Similar traits could be found in urodeles, which are generally thought to represent a derived condition among chordates (Francis, 1934; Paterson, 1939).

In the African clawed frog, Xenopus laevis, the maxillary nerve tends to be diminished and a well-developed ophthalmic nerve innervates the rostral end of the upper jaw, as seen in urodeles (Paterson, 1939). The condition as such, in which the ophthalmic nerve takes over the maxillary nerve's innervation pattern, is specific to the Pipidae including Xenopus. This phenomenon is regarded as an autapomorphy of anurans (Paterson, 1939). However, in other frog genera such as Rana and Leiopelma, the maxillary nerve is divided into two rami mediolaterally, of which the medial one makes communication with the palatine branch of VII (Stephenson, 1951). The latter pattern is also observable in Discoglossus pictus (Schlosser and Roth, 1997a) and Eleutherodactylus coqui (Schlosser and Roth, 1997b).

In the Gymnophiona, the sister group of anurans and urodeles, part of the maxillary nerve passes along the palatine branch of VII (Maddin, 2011), although its exact innervation domain has not been examined (Wiedersheim, 1879; Waldschmidt, 1887).

In dipnoans (e.g., Neoceratodus forsteri), the maxillary nerve divides mediolaterally into two branches during development, of which the medial one communicates with the facial nerve (Bartsch, 1993). Distally, this nerve reaches the ventral aspect of the ethmoidal cartilage, resembling the mammalian nasopalatine nerve. However, the presence of the nasopalatine nerve was uncertain in anatomical analyses of Protopterus annectens (Pinkus, 1895). Similarly, anatomical observations of the coelacanth (Latimeria chalumnae) have also not identified the nasopalatine nerve (Northcutt and Bemis, 1993).

As noted above, the origin of the mammalian nasopalatine nerve remains uncertain. However, the rostral part of the so-called maxillary nerve in the shark and a major part of the upper branch of the maxillomandibular nerve in the sturgeon that does not innervate the upper jaw exhibits conspicuous similarity to the nasopalatine nerve in mammals (Fig. 9A). All these nerves leave the maxillary process and supply the postoptic region of the premandibular domain. Thus, the nasopalatine nerve is more likely to represent a plesiomorphic feature among gnathostomes. Also in holocephalans, the sister group of the Elasmobranchs, the maxillary nerve divides into two branches, of which the medial issues fine nerves to innervate the nasal sac. Of those, a few further extend rostrally to reach the region around the nostril to innervate the skin and muscles in that region (Cole, 1896). The latter nerve resembles the rostral component of the maxillary nerve in sharks, especially with the lack of upper jaw innervation. As was implied by the developmental pattern in the sturgeon, the nasopalatine nerve might even develop as a major component of the upper branch of the maxillomandibular nerve (Fig. 9A). Namely, the part of V2 that is restricted to the maxillary process develops to innervate this gnathostome's autapomorphic domain. Thus, the condition in some amphibians and diapsids might represent derived conditions among the entire gnathostomes.


Figure 9. Proposed scheme of the evolution of the trigeminal nerve. A: The maxillomandibular ganglion and the maxillary nerves are colored orange and the mandibular arch derivatives light blue. During evolution, the maxillomandibular nerve ancestrally supplied not only the mandibular arch derivatives but also the postoptic region of the premandibular domain. The chicken and gecko do not have a nasopalatine nerve, but this condition would have been established secondarily in the diapsid lineage. B: The schematic development of the maxillomandibular nerve in the gnathostome embryo. C: The trigeminal nerve innervation patterns in lamprey (stage 28 embryo). Redrawn from Kuratani et al. (1997). D: The schematic developmental pattern of the maxillomandibular nerve in the lamprey. For abbreviations, see the list in the text.

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It has long been known that in sturgeons, whose jaws are released from the neurocranium and are derived solely from the mandibular arch, there is an extensive innervation of the rostrum and associated structures by the so-called “maxillary nerve” (Norris and Hughes, 1920; Allis, 1923; Norris, 1925; Sewertzoff, 1928; Marinelli and Strenger, 1959, 1973; Takahashi and Kobayashi, 1989; Kardong, 2008). As shown in Figures 6C,D′ and 7D,E, the nerve innervating the upper jaw in these animals arises as a branch of the mandibular nerve, as the best example to exhibit decoupling of this nerve from the rest of the maxillary nerve (although the latter no longer innervates the upper jaw). Furthermore, the nasopalatine nerve in these basal jawed vertebrates appears to show its nature as a principal component of the trigeminal nerve, because decoupling of the maxillary process from the premandibular domain does not appear to have arrested the axonal growth and innervation of the nasopalatine nerve. The dual nature of the maxillary nerve is apparently shared by other vertebrate species, as seen in the bifurcation of the maxillary nerve into medial (nasopalatine) and lateral components (maxillary process-related maxillary nerves). In the above scheme, that part of the maxillary nerve restricted to the maxillary process derivatives should more appropriately be termed the “palatoquadrate” nerve to distinguish it from the rest of the maxillary nerve, the nasopalatine nerve. Thus, the previously defined maxillary nerve consists of nasopalatine and palatoquadrate nerves anteroposteriorly, and the latter can occasionally merge with the mandibular nerve, as seen in the sturgeon.

A characteristic pattern of the palatoquadrate nerve in the sturgeon is that, unlike in other gnathostome species, some fibers take the course of the nasopalatine nerve for their proximal part. These fibers branch off from the nasopalatine nerve ventrally to enter the upper jaw (Fig. 6D,D′). This is reminiscent of some communicating fibers observed between the maxillary process and premandibular palatal domains in other embryos (Fig. 2D′). As for the formation of the common nerve trunk for the mandibular and palatoquadrate or maxillary nerves, similar morphological patterns have been observed among some osteichthyan stem groups (Allis, 1897; Norris, 1925). The flexibility or violation of the boundary between embryonic compartments in the proximal growth of the palatoquadrate nerve as described above would be most similar to the pattern observed in the avian chorda tympani (internal mandibular nerve of VII; Kuratani et al., 1988 and references therein); in the chicken this nerve mainly takes a pretrematic course. For most of the peripheral nerve branching patterns, growth of the nerve fibers is primarily confined to the craniofacial primordia, as typically seen between the medial and lateral nasal prominences and the maxillary process. However, such a restriction does not appear to be rigid along the longitudinal boundary to limit the maxillary process and the premandibular ectomesenchyme mediolaterally, where a number of fibers form communications between different nerves (Figs. 4B′–D′ and 5C′,D′). The ophthalmic nerve branches also grow secondarily across a similar boundary from the lateral aspect and innervate the upper incisors in diapsids. It is conceivable that this type of developmental variability would also have led to evolutionary variations, which is actually the case in the morphological patterns of the nerves innervating the palate.

As described in the result, in shark, the palatine branch of the VII does not communicate with trigeminal nerve branches whereas in other gnathostomes the communications are established between those nerves. This trait also has been reported that the palatine branch of VII in other shark species such as Chlamydoselachus anguineus, Cephaloscyllium umbratile, or Squalus acanthias, or in rays such as Dasyatis akajei, Raja kwangtungensis, or Mobula diabolus, resembles that of S. torazame, especially in their innervation of oral roof mucosa and upper jaw teeth (Allis, 1923; Takahashi and Kobayashi, 1989). This trait of the palatine branch appears to be a common trait among elasmobranchs. On the other hand, the palatine branch of VII in the holocephalans passes the oral roof and ventral aspect of the nasal sac and then turns caudally to innervate the upper jaw teeth, unlike in the shark (Cole, 1896). It remains unknown if this nerve is truly analogous to the palatine branch in other gnathostome groups.

Craniofacial Development and Evolution of the Trigeminal Nerve

Based on these comparisons, our proposed evolutionary sequence of trigeminal nerve morphology is summarized in Figure 9A. The gnathostome craniofacial region develops from the mandibular arch-derived maxillary and mandibular processes as well as from more rostral primordia that are divided by a pair of nasal pits into the medial and lateral nasal prominences (Johnston, 1966; Kuratani and Tanaka, 1990; Fig. 9B). These processes are formed by the neural crest cell stream that migrates rostral to the eye (preoptic crest cells; Kuratani et al., 2001). The rostral part of the upper jaw in many gnathostomes, such as the intertrabecula (the rostral part of the trabecula), the premaxillary bone that carries the incisors in mammals, the nasal capsules and nasal septum are derived from this cell population (Depew et al., 2002; Lee et al., 2004; Ozeki et al., 2004; Minoux and Rijli, 2010; Talbot et al., 2010; Wada et al., 2011; Gillis et al., 2013). There is another cell population that tends to be neglected among the premandibular crest cells populating the postoptic domain, which later differentiates into the caudal part of the trabecula (Cerny et al., 2004; Lee et al., 2004; Wada et al., 2005, 2011; reviewed by Kuratani et al., 2012).

Of the trigeminal nerve branches, the ophthalmic nerve predominantly innervates the premandibular components, and the maxillomandibular nerve innervates the mandibular arch derivatives. However, the preoptic domain is primarily a doubly innervated area whose ventral side is primarily innervated by the upper branch, the nasopalatine nerve, of the maxillomandibular nerve. Compartment-dependent restriction is only clear between the derivatives of the nasal prominences and maxillary process. Given that the maxillary prominence apparently represents a secondary formation utilized to acquire dorsoventrally biting jaws, the nasopalatine nerve might rather represent an ancestral component of the maxillomandibular nerves (Fig. 9B).

In this regard, it would be worthwhile considering the morphological pattern of the trigeminal nerves in cyclostomes (lampreys and hagfishes), a sister group of the gnathostomes. Anatomical comparisons between cyclostomes and gnathostomes have been attempted by many: the basic morphological patterns of cranial nerves are shared between the cyclostomes and gnathostomes, and the cyclostome trigeminal nerves are also divided into ophthalmic and maxillomandibular components (Alcock, 1898; Sewertzoff, 1931; De Beer, 1937; Marinelli and Strenger, 1954, 1956; Ronan, 1988; Mallatt, 1996, 2008; Oisi et al., 2013). The trigeminal nerve innervation domain in the lamprey is embryonically filled with the rostralmost cephalic crest cell population, also called the trigeminal crest cells in this animal (Horigome et al., 1999; McCauley and Bronner-Fraser, 2003; reviewed by Kuratani et al., 2001). The mandibular arch is again identified and molecularly specified as the Hox gene code-default domain among the pharyngeal arches (Takio et al., 2004). The maxillomandibular nerve of the lamprey and hagfish also possesses upper and lower branches, often called the maxillary and mandibular nerves (Alcock, 1898; Johnston, 1905a; Sewertzoff, 1931; De Beer, 1937; Marinelli and Strenger, 1954, 1956; Ronan, 1988; Mallatt, 1996, 2008; Kuratani et al., 1997; Fig. 9C). However, given that the gnathostome jaw was obtained through systematic reorganization and repatterning of the craniofacial ectomesenchyme, the latter terminology is inappropriate: the upper and lower lips of the ammocoete larva do not correspond to the upper and lower jaws of gnathostomes (Shigetani et al., 2002; reviewed by Kuratani, 2012 and Kuratani et al., 2012). In particular, the upper branch of the maxillomandibular nerve (called “V23a” by Oisi et al., 2013) contains not only sensory fibers, but also motor fibers to innervate the mandibular arch-derived upper lip muscles (Koyama et al., 1987; Kuratani et al., 2004; Murakami and Kuratani, 2008; Oisi et al., 2013).

In the lamprey oral apparatus, the upper lip contains postoptic neural crest cells that are not utilized as a component of the oral region in gnathostomes (reviewed by Kuratani, 2012 and Kuratani et al., 2012; Fig. 9D). Nevertheless, it is worth mentioning that the upper lip environment is similar to the region where the proximal part of the gnathostome nasopalatine nerve passes and communications are established between this nerve, and the palatoquadrate and palatine nerves. In other words, in the cyclostomes, the boundary is violated by the maxillomandibular nerve fibers between the mandibular arch derivatives and the premandibular domain, if the exact homologue of the nasopalatine nerve is absent from the lamprey. These lines of evidence suggest that the maxillomandibular nerve in vertebrates has always possessed both upper and lower trajectories (i.e., a shared feature of vertebrates), of which the upper primarily extended into the premandibular domain (preoptic or postoptic regions) in agnathan vertebrates. Thus, in a narrow sense, the maxillary nerve evolved when the maxillary process emerged as a new structure in the acquisition of the jaw in the lineage of late gnathostomes.


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  9. Supporting Information

The authors are grateful to Kiyoshi Hiraoka of Fujikin, Tsukuba, Japan for providing Bester embryos; Kazuko Yamamoto, Shigemi Shibuya, and Tamami Hirai for the maintenance of the aquarium tanks and collection of shark embryos; Miyuki Noro for providing gecko embryos. The authors also thank Hiroshi Nagashima for technical advice on immunohistochemistry and paraffin sectioning; Yasuhiro Oisi for advice on the AVIZO technique; Tatsuya Hirasawa and Christian Mitgutsch for their critical reading of the manuscript, and Masaki Takechi and Noritaka Adachi for their technical support and advice.


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