In today's fast-paced world of scientific discovery, it is sometimes difficult to carefully examine old discoveries and important classical models of development, particularly if the published research is not easily obtained electronically. The aim of this review is to highlight some of the historically relevant discoveries in cranial placode research, with a particular focus on the neurogenic placodes. By examining the research timeline and the conclusions drawn from the scientists who made key discoveries, we may be able to gain a clearer view of how the current models of neurogenic placode development were formed.
In vertebrates, the tissues that contribute to special sense organs and cranial ganglia originate primarily from the surface ectoderm in the head. In the case of the lens, nasal epithelium and ear, defined regions of head ectoderm acquire a thickened epithelial appearance, marking the first histological evidence of where they will form. These thickenings were first documented in the mid to late 19th century by pioneering developmental biologists (see below) and referred to as placodes. Thickened placodes, such as the olfactory and otic (which contributes multiple cell types), generate sensory neurons as part of their development program, and are therefore categorized as neurogenic placodes. Several other regions of cranial ectoderm also generate sensory neurons, and while in some cases their histology may not be distinguishable from the surrounding surface ectoderm, these regions have also been categorized as neurogenic placodes. Neurogenic placode cells are typically specified from within a competent domain of cranial ectoderm via signals from their surrounding environment, and then delaminate from the surface ectoderm as neuroblasts, ultimately grouping together by themselves or with nearby neural crest cells to form the cranial ganglia (Figure 1). The fish lateral line system also originates as cranial neurgenic placodes, where cells then migrate as a mass caudally, depositing neuromasts along the way. For the past two decades, significant advances have been made in our understanding of the molecular programs responsible for neurogenic placode development. All of the common developmental signaling pathways have been characterized in one or more neurogenic placodes. Important transcriptional regulators of the pre-placodal domain and the individual placodes have been identified. As placode research advances in the coming years, additional molecular regulators will likely be discovered, new interactions of signaling pathways will be uncovered, and cell biological process necessary for delamination and differentiation will become better characterized. As we move forward, continually navigating the breadth of relevant molecular data found in the literature today, a retrospective look at how we arrived at our current understanding of neurogenic placode development may provide the needed perspective to achieve novel discoveries.
Descriptive origins of placode research in fish, amphibians, birds and mammals
The first well-documented descriptions of cranial placodes came in the late 19th century. Citations of these early studies are scattered throughout the literature, including elegant summaries such as a 1992 book chapter by Kristine Vogel (Chapter 9 in Scott, 1992). Pioneering developmental neuroscientists such as Van Wijhe (1882), Froriep (1885), Beard (1888), von Kupffer (von Kupffer, 1891; von Kupffer, 1895; Kupffer, 1900) and Strong (1895) established important first descriptions of placode location, early neurogenesis, and sensory contributions from the placodes and neural crest in fish and amphibians. As an example, the leading sentence of von Kuppfer's description of cranial nerve development, based on his studies in Lamprey, effectively described neuroblast formation from epibranchial placodes (von Kupffer, 1891). He states, “Tracing their origins, these cells are seen to proceed from the epidermis. The latter thickens by elongation of its elements, which then divide transversely, after which the ental layer of daughter cells do not reassume their epithelial arrangement, but constitute the special sub-epidermal layer of neurodermis.” These observations were made without the advanced equipment and markers available to us today. Interestingly, the modern description of epithelial-to-mesenchymal transition (EMT) seen in neural crest and cancer cells has intermittently been characterized as the mechanism of cellular movement in placode cells. However, more careful analysis by Graham et al. (2007) clarified, with modern molecular markers and techniques, that the process occurs more in line with von Kupffer's descriptions.
Near the turn of the century, additional contributions followed, with Francis L. Landacre establishing himself as a leader in the field by characterizing placode and sensory neurogenesis in additional fish species and in amphibians (Landacre, 1907; Landacre, 1910b; Landacre, 1910a; Landacre, 1912; Landacre and McLellan, 1912; Landacre, 1916). While much of his work was descriptive, it broadened the knowledge of similarities and differences across species. In his publication on ganglia development in the catfish Ameiurus, the difficulties faced due to available methodologies were highlighted in the following from his introduction: “The attempt to account for the fate of all embryonic cell masses, a part of which may go to form ganglia, presents a totally different problem and one with which we are unable to cope with present technical methods.” This study was a massive attempt to finally characterize the details of cranial ganglia formation at every available developmental stage. More than 80 camera lucida drawings of thin sections were included to support the descriptions (Landacre, 1910a). While the data and descriptions were important for establishing precise locations of placodes and clarifying differences and similarities between species, in my view the most important contribution found in this publication is his extensive summary of the historical literature on ganglia development known at that time, where he identified several 19th century studies not cited here (some not being available, or only available in German), but were important preparatory studies for his work and that of others. Landacre also showed great interest in the relationship between cellular origin and neuronal function, and was later credited with originating the concept of functional specificity among the different placode types (Batten, 1957c).
Contemporary with these early fish and amphibian studies, a small body of research described avian neural crest and placodes (reviewed in Vogel's chapter 9 of Scott, 1992), although the early research in birds seemed to be more broadly focused on general descriptions of amniotic development and embryogenesis. In subsequent years, as will be discussed later, the avian model proved very valuable in defining the cell biology of placode development.
Neurogenic placode research in mammals was apparently controversial through the first half of the 20th century, with conflicting reports complicating a firm consensus as to whether cranial ganglia derived solely from the neural crest, or if surface ectoderm also made a contribution. This conflict was well-summarized by Batten, as he introduced his histological descriptions of placode development in sheep (Batten, 1957a). An excerpt is provided as an example of the conflicts that existed at the time:
As early as 1885 Froriep noted the intimate fusion of thickened epibranchial ectoderm with the ganglia of nerves VII, IX and X in bovine embryos, but failed to find any similar sites in contact with the ganglion of nerve V. Chiarugi (1897) described the intervention of ectodermal cells in the formation of the trigeminal ganglion in the guinea pig, while in the same species Da Costa (1931) finally reached a negative conclusion after re-examining his earlier results (1923, 1925). The reality of the process of placodal budding in the squirrel has been accepted by Volker (1922), but denied by Weigner (1901), who considered that the ganglion developed exclusively from the neural crest.
In this same study, Batten describes small (up to 12 cells) and larger (20 to 36 cells) ectodermal “thickenings” in an extensive area associated with the trigeminal, a placode that is widely considered histologically indistinguishable from the epidermis. This observation is generally in agreement with later descriptions aided by the trigeminal placode markers Pax3 and Fgfr4 (Stark et al., 1997). Batten should be applauded, since picking out areas of placode cell generation without guiding markers would have been challenging. Concurrent studies by Batten looking at individual epibranchial placodes and the associated ganglia also helped to improved mammalian anatomical descriptions of placodes and the generation of neurons from them (Batten, 1957b; Batten, 1957c; Batten, 1957a; Batten, 1958; Batten, 1960).
The amphibian model and early experimental approaches in placode research
Hans Spemann was a pioneering innovator of experimental embryology in vertebrates. Some of Spemann's early transplantation experiments examined the question of lens induction (Spemann, 1901), where he demonstrated that lens formation was dependent on adjacent optic cup tissue. Subsequently, important placode transplantation experiments done by Stone in amphibians expanded the work to include the neurogenic placodes, with his initial focus on cranial ganglia and the lateral line development after placode ablation (Stone, 1922), and on the fate of ophthalmic placode tissue when transplanted heterotopically (Stone, 1924). Included in this paper were amazing three-dimensional drawings of the resulting ganglia, manually rendered by visually assembling images of histological sections. Ectopic ganglia were observed, showing that in some cases cells were able to differentiate after transplantation to a new environment. During the subsequent 15 year period, these initial experiments were replicated with other placodes and cranial tissues, laying a strong foundation for understanding developmental processes through experimental manipulation, and lending validity to this approach in sensory systems research (Stone, 1928a; Stone, 1928b; Stone, 1933; and Stone, 1937 as examples).
Following Stone, another well-cited researcher, Edgar Zwilling, commenced his doctoral studies in experimental embryology using an amphibian model to examine inductive requirements for the olfactory and otic epithelia (Zwilling, 1940; Zwilling, 1941). Zwilling must have also been influenced by Waddington (discussed later), as his subsequent research primarily used the chick embryo model, including studies of mutant lines, and experimental approaches to examine limb and tail development. At the same time, Chester Yntema began contributing significantly using both amphibian and avian systems. He published experimental work on ear induction using the salamander model Amblystoma punctatum. Some of his important contributions included defining the potential of ectoderm to make otic tissue at different stages (Yntema, 1933), examining the commitment of otic ectoderm to an ear fate (Yntema, 1939), and a culminating work describing a stage-specific map of potential inducing tissues, as well as tissues competent to make the otic placode (Yntema, 1950). This last study highlighted an important transition of this region of ectoderm, being fated away from neural tissue induction and toward ear induction over time. In his discussion, Ynetema emphasized a stepwise process for otic placode formation that begins with 1) the migration of the “mesentoderm” to underlie the presumptive otic placode for early induction, 2) the subsequent interaction with the neural folds for secondary activation, and 3) the proper response (competence) of the overlying ectoderm. He showed that all the tissues involved have maximal inducing (or competence) properties only at certain times of development. While Amblystoma is an atypical model for placode development research today, it would be valuable to carefully assess current molecular data in relationship to his detailed analysis of the spatiotemporal restriction of inducing tissues and competent ectoderm. Yntema contributed several other publications, some focused on fate mapping the neurogenic placodes in amphibians (Yntema, 1937; Yntema, 1943), with additional experiments in birds yielding a clearer picture of neurogenic placode origins and contributions in amniotes (Yntema, 1944). In fact Yntema had a long and diverse career, examining several important but seemingly unrelated questions using the chick embryo model, and later spent over a decade describing unique features of turtle development.
Finally, when looking at past contributions to placode research in amphibians, it is important to highlight another key contributor of experimental data – Antone Jacobson, one of the more highly cited researchers in this field. He performed many grafting, transplantation, and rearrangement experiments in amphibians to test placode induction, focusing significant work on clarifying lens induction (Jacobson, 1955; Jacobson, 1958; Jacobson, 1963a; Jacobson, 1963b; Jacobson, 1963c; Jacobson, 1966). His combined work was more refined and detailed in developmental timing and precise tissue grafts than the classical experiments performed decades earlier, and included more robust analyses and graphical reporting of results. In his 1966 publication in Science, he summarized graphically a complex body of work aimed at describing lens placode induction. It is clear that Jacobson, like Yntema, understood the concept of induction as being a stepwise process involving multiple tissues. Interestingly, today's ambitions to identify the inducer are not new ones. Jacobson in fact emphasized caution when he wrote:
It would be well if we knew when, or even if, induction begins and ends, as it is very difficult to untangle induction processes from other processes that occur before and after them or concurrently with them. Embryonic induction is part of a continuum of developmental processes. But the concept of induction, once separated out and named, has suffered reification. A number of papers imply or refer to “the moment of induction,” and attention has prematurely shifted from study of the process of embryonic induction to a search for “the inductor substance.”
Reification (reify) is to regard (something abstract) as a material or concrete (“Reify.” Merriam-Webster.com. Merriam-Webster, n.d. Web. 14 Mar. 2014. http://www.merriam-webster.com/dictionary/reify). While Jacobson himself sometimes fell prey to objectifying the concept of induction, acknowledging this tendency with caution revealed his desire to conceptualize development as spatiotemporal processes, not as concrete components or objects.
Chick embryology and placode discoveries in the longstanding model for nervous system development
While significant work was continually being done in amphibians, key paradigm shifts in research also occurred due to significant discoveries in the avian model. It is important to highlight that while amphibian models were, for vertebrates, the primary organism for experimental embryology research in the first half of the 20th century, the chick embryo model was also well-recognized. This is often overlooked, since the foundational chick embryo citation used today is the 1951 Hamburger and Hamilton staging guide. Several decades earlier, however, the chick was a core model for the instruction of vertebrate embryology. To quote Bradley Patten (Patten, 1929), “The fact that chick embryos are so generally used as a laboratory material for courses in vertebrate embryology seems to warrant the treatment of their development in a book designed primarily for the beginning student.” One of the first detailed references for chick embryo research and teaching was Frank Lillie's book The Development of the Chick (Lillie, 1908), where in his preface to the first edition, he states: “This book is a plain account of the development of the never-failing resource of the embryologist, the chick.” It is clear that contemporary to the early studies in fish and amphibians, embryologists were also actively characterizing chick embryo development, including that of the nervous system. Lillie's book has gone largely overlooked in recent decades despite the fact that (Hamburger and Hamilton, 1951) relied heavily on descriptions documented in this foundational work. While only brief mentions of placodes are referenced in Lillie (1930 ed.), neural crest development is well-described, as are the general characteristics of cranial ganglia development. These early descriptions were important for later work characterizing nervous system development in the chick.
While experimental manipulation was primarily being done in amphibian models, an important and often-referenced study on otic placode induction in chick was published by C. H. Waddington in 1937. This paper was pioneering on more than one front. First, it was one of several studies published in the 1930s by Waddington that gave validity to experimental approaches in chick, in this case by evaluating otic placode origins (induction) through experimental extirpation of presumptive ear ectoderm and adjacent tissue. Second, it described basic principles of placode induction in chick. Finally, it highlighted Waddington's keen understanding of how tissue interactions shaped developmental processes (Waddington, 1937). Perhaps surprisingly, ideas that are sometimes considered novel today were appreciated long ago, as indicated by the following excerpt describing the experiment to remove the neural folds adjacent to presumptive otic ectoderm:
“…The operation should have removed the neural tissue which might be supposed to be the inducer of the ear vesicle, leaving the presumptive ear ectoderm untouched.One could only expect the operation to suppress the formation of the ear if (1) the ear ectoderm, at the time of the operation, was not capable of forming an ear when isolated, and (2) the neural tissue which was removed was the only tissue capable of endowing it with this capacity.”
Even questions of competence were thoroughly explored by Waddington. When musing on the results of presumptive otic placode ablation, he wrote, “The material from which the regenerated ears are formed presumably comes from the ectoderm surrounding the wound…” and later stating, “Since new ear vesicles can be induced in the non-presumptive ectoderm…it is clear that it should be possible to induce ear formation in a more enlightening way…” Waddington tested this by grafting neural fold tissue beneath midbrain-level ectoderm. The predominant failure to induce ears, along with his aforementioned discussion of the neural fold extirpation results, led to the conclusion that “several factors must play a part in the determination of the ear vesicle.” Fast-forward 75 years from Waddington to today's abundance of molecular data on ear induction, it is now confirmed (as it was proposed then) that “several factors” are required for ear induction. While it is certainly true that Waddington's work has been examined and cited for its relevance to otic placode competence and induction, it is important to occasionally review again old data as we develop new developmental models to test experimentally.
Two decades later, through extirpation experiments performed in chick by Victor Hamburger, placode and neural crest contributions to the trigeminal ganglion were more clearly defined (Hamburger, 1961). This work helped to clarify, by experimental manipulation, the leading theories on placode and neural crest contributions and their level of interdependence for subsequent neuronal differentiation and target innervation by trigeminal sensory cells. He showed that for trigeminal sensory neurons, the neural crest was required for proper ganglion location, while cells from the placodes were needed for proper differentiation and innervation of peripheral targets. The developmental stage and precise anatomical location of Hamburger's ablations left somewhat unclear the likelihood of placode regeneration, and placode cells making central connections in the absence of the neural crest. Moody and Heaton (1983b) helped clarify this by concluding that ablation resulted in a delay in overall development. Significant follow-up work on this question is well-summarized in the thorough review by Baker and Bronner-Fraser (2001). An earlier reference by Noden (1978b) also stated that placode cells are able to establish normal central projections, citing Székely (1959b). George Székely, like Landacre, made impactful contributions on functional specificity of neurons after heterotopic transplantation of various tissues, such as placodal precursor tissue. In Székely (1959b), transplantations of the “ganglion anlage” (trigeminal placode) in place of the vagus placode and visa-versa were analyzed carefully for responses to tactile stimulation. Upon review of the text, I found that Székely discussed the results of his transplantation experiments in good detail, with significant focus on factors that might influence the central axon projections, and how the anatomy might dictate projection tracts. Noden again references this paper in a later review, describing a ‘corneal’ (trigeminal) response (Noden, 1993), which in fact seems to be referring to vagal-derived neurons grafted into the trigeminal (see figure 1 in Székely, 1959b). It is interesting to note that a different Székely reference describing transplantation of limb tissue or the larval eye, not placode tissue, also sometimes surfaces in this discussion (Székely, 1959a). This reference can easily be found via standard online literature searches, while the more relevant paper (Székely, 1959b) is not indexed in any of the standard databases, highlighting one of the difficulties in referencing some of the older literature.
The research described above was accomplished without many of the common tools for cellular identification that we rely on today. Despite this void in available tools, many leading theories proposed by the scientists mentioned have persisted, being verified by 1) quail chick chimera data, 2) molecular markers of placode precursors and differentiating neurons, and 3) experimental manipulations to test theories of induction, competence, determination and molecular networks that instruct the differentiation process.
Visualizing placode development through cellular and molecular markers
An important breakthrough in what some would consider descriptive embryology was made with the advent of the quail-chick chimera. The observations of Nicole Le Douarin in the late 1960s and early 1970s that quail cell nuclei differed in their appearance due to heterochromatin condensations in the nucleoli (Le Douarin, 1969; Le Douarin, 1970; Le Douarin, 1971), and her subsequent application for fate mapping via transplantation of quail tissue into developing chick embryos (Le Douarin, 1973; Le Douarin and Teillet, 1973; Le Douarin, 1974; Le Douarin and Teillet, 1974) created an important paradigm shift in vertebrate developmental biology research. Her applications were often used for studying lineages of the nervous system, and became critical in mapping fates of neural crest cells. Others soon adopted the quail-chick chimera approach for diverse fate mapping studies. One in particular was Drew Noden, who, along with important colleagues, was an expert developmental neuroscientist devoting a significant part of his work to; 1) mapping axonal projections using a classical HRP method (Noden, 1980b; Noden, 1980a; Covell and Noden, 1989), 2) clarifying the timing of neural crest and placode terminal differentiation (d'Amico-Martel and Noden, 1980; D'Amico-Martel, 1982), and 3) characterizing important roles of the neural crest in embryo patterning and development (Noden, 1978a; Noden, 1978b; Noden, 1980b; Noden, 1983; Noden, 1984; McClearn and Noden, 1988). In 1983, Noden applied the quail-chick chimera approach to detailing the neural crest and placodal origins of the cranial ganglia (D'Amico-Martel and Noden, 1983). This landmark paper provided the data for figures that appeared in later reviews (Noden, 1993; Webb and Noden, 1993). These figures have been replicated many times in subsequent papers and reviews on placode development (see figure 1).
The next key to advancing studies in neuronal cell fate determination was the discovery of various molecular markers. An excellent review by Baker and Bronner-Fraser (2001) lists important markers for placodes and related tissues available until that time. For example, HNK-1 was first described by Vincent and Thiery (Vincent et al., 1983; Vincent and Thiery, 1984) for its usefulness in labeling the neural crest (see also Bronner-Fraser, 1986). This marker greatly simplified tracking neural crest cells, which had previous been done by morphological criteria. Another important marker for lineage studies was the quail-specific marker QCPN, maintained by the Developmental Studies Hybridoma Bank (DSHB). After the landmark papers on quail-chick chimera experiments by Le Douarin and others, efforts were made to identify quail-specific antibodies to simplify cellular identification. In 1987, Solursh, who earlier had developed techniques for immunofluorescent imaging of tissue samples (Solursh et al., 1982a; Solursh et al., 1982b) and helped establish the DSHB, used a quail-specific antibody to identify vascular endothelial cells (Solursh et al., 1987). Several other antibodies were characterized as useful in chimera experiments (Aoyama et al., 1992, for example), but these were cell-type specific antibodies, and not general markers of all quail cells. QCPN began to be used in the mid-1990s as the standard for avian chimera studies, and has greatly simplified analysis of quail-chick chimera experiments. For neuronal studies, the discovery of β-III-tubulin as a marker of differentiating neurons (first used to characterize trigeminal neurons) was another key advancement (Moody et al., 1989a). Using this marker, along with others, Sally Moody contributed significantly to our core understanding of trigeminal nerve development, and to techniques in epitope detection for peripheral nervous system research (Heaton and Moody, 1980; Moody and Meszler, 1980a; Moody and Meszler, 1980b; Moody and Heaton, 1983a; Moody and Heaton, 1983c; Moody and Heaton, 1983d; Moody and Heaton, 1983b; Riggott and Moody, 1987; Moody et al., 1989b).
While thickened placodes such as the lens and otic could be studied through experimentation with a morphological readout, cell type-specific markers for individual placodes were still needed. Without good molecular markers of trigeminal and epibranchial placodes (and even subpopulations of cells within the otic placodes), proper readouts of cell fate could not be determined. Understanding neurogenic placode development, from questions of competence and induction to delamination and differentiation, required better visualization through molecular markers. Several markers became available in the early 1990s, allowing experimental studies in the chick to specifically address these core questions of cell fate determination. With the identification of Pax3 as a marker of the ophthalmic trigeminal placodes (Stark et al., 1997), data began to accumulate toward clarifying the developmental requirements for opV placode-derived neurons. Importantly, classical experimental approaches were combined with marker readouts to test the core questions of induction, and later competence, specification and commitment toward the placode fate (Baker et al., 1999). Parallel work on epibranchial placodes became possible with the utilization of Phox2a as an endogenous marker (Begbie et al., 1999). This study determined that pharyngeal endoderm and not neural crest was responsible for a key induction step. Importantly, unlike in prior work on the trigeminal placode, an inducing factor, BMP7, was identified as required for mediating epibranchial placode formation. While Jacobson might have argued for characterizing the process rather than identifying the inductor substance, it was a significant breakthrough in neurogenic placode research. While not a particular focus of this review, a renewed focus on otic placode development soon surged as many excellent studies aimed to understand the molecular cues that govern the several cell types derived during otic development. Much of this rekindling was dependent on the development of several important early markers of the otic placode and surrounding tissue (Baker and Bronner-Fraser, 2001).
The application of molecular markers has also extended earlier in development with work aimed at characterizing the preplacodal/panplacodal domain, a region of competent head ectoderm adjacent to the neural folds that is specified early during initial head formation. This is a very active field of research today. A sequence of review articles cited here highlights important early discoveries in defining and characterizing this domain (Baker and Bronner-Fraser, 2001; Streit, 2004; Schlosser, 2006). Fate mapping studies, including many referenced here, predicted this domain, however without molecular markers to identify uniquely differentiating cells from within a morphologically homogeneous epithelium, it was impossible to move the research forward. One of the early experimental applications in preplacodal domain research that wedded classical labeling techniques with early placode markers examined the overlapping domains of the lens and olfactory placodes (Bhattacharyya et al., 2004). Here, early labeling showed a common lineage for the two placodes, while Dlx5 and Pax6 were analyzed for their temporal changes during and after cellular segregation. Transcription factors expressed early, such as Six and Dlx family members and Eya, along with placode-specific markers such as Pax family members, have significantly advanced our knowledge of the placode precursor population (also reviewed in Grocott et al., 2012). A recent review article (Saint-Jeannet and Moody, 2014) highlights the current knowledge in preplacodal domain research.
Genetic and molecular manipulation to understand placode development
While Jacobson warned against compartmentalizing developmental processes into specific time points dependent on one or a few inducing factors, today's advances into molecular genetics have significantly changed experimental opportunities. We can, in fact, know the impact of a particular signaling ligand or transcription factor on cell fate. In placode research, gene function first began to be characterized through a few known mutants and some early knockouts in mice. Noden and Van De Water (Noden and Van De Water, 1992) summarized ear defects from observations made in two different knockouts of the mouse Hox 1.6 (Hoxa1) gene. Hoxa1 had only been described five years earlier (Baron et al., 1987), and the knockout papers that described them were among the first using homologous recombination (Lufkin et al., 1991; Chisaka et al., 1992). Prior to this, only naturally occurring mutants such as Splotch (Pax3 mutation) had been characterized for peripheral nervous system and sensory organ defects. Other spontaneous mutations where gene identity had been determined were also being characterized, such as FGF-3 as a potential ear inducer based on NT expression and defects in kreisler mutant and FGF-3 knockout mice (Mansour et al., 1993; McKay et al., 1996). Soon, gene knockouts were being generated in mice specifically to look at gene function in the developing nervous system, with some, such as Phox2a (Morin et al., 1997), showing defects in cranial ganglia. Many discoveries have since been made using the mouse model.
Returning to the chick, electroporation strategies were developed in the late 1990s, and many signaling pathways and transcriptional regulators have since been studies through targeting gene constructs to the various placodes in chick embryos. The advantage of embryo accessibility, combined with the many tools available using chick electroporation, continues to yield important new data on cell signaling and transcriptional regulation in neurogenic placode development.
Zebrafish labs have also contributed important data about molecular regulation of placode development, particularly in describing lateral line development. Some descriptive studies arose in the 1980s (Metcalfe, 1985; Metcalfe et al., 1985), and detailed fate mapping studies were performed later (Collazo et al., 1994; Alexandre and Ghysen, 1999). Major breakthroughs in discovering gene function in lateral line development came from genetic screens that lifted zebrafish to the model organism it is today (Whitfield et al., 1996; Nicolson et al., 1998, as early examples). Since then, many studies have combined to effectively described lateral line morphogenesis and important gene regulators of lateral line development (reviewed in Ghysen and Dambly-Chaudiere, 2007; Chitnis et al., 2012). The lateral line has more recently been used as a model for understanding general questions of morphogenesis and cell migration (reviewed in (Aman and Piotrowski, 2010; Aman and Piotrowski, 2011), and for chemical screens for drug discovery (reviewed in Ou et al., 2012). Zebrafish has clearly evolved as an important model for sensory neurogenesis.
While not discussed here, molecular work done in Xenopus has also provided an important contribution (Schlosser, 2006). The combined data from the several model systems has clarified the timing, tissue interactions, and gene regulation events that are needed to make neurogenic placodes and their derivatives.