These authors contributed equally to this work
Expression patterns of the ADAMs in early developing chicken cochlea
Article first published online: 18 MAR 2013
© 2013 The Authors Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists
Development, Growth & Differentiation
Volume 55, Issue 3, pages 368–376, April 2013
How to Cite
Lin, J., Yan, X., Wang, C., Talabattula, V. A. N., Guo, Z., Rolfs, A. and Luo, J. (2013), Expression patterns of the ADAMs in early developing chicken cochlea. Development, Growth & Differentiation, 55: 368–376. doi: 10.1111/dgd.12051
- Issue published online: 10 APR 2013
- Article first published online: 18 MAR 2013
- Manuscript Accepted: 4 FEB 2013
- Manuscript Revised: 29 JAN 2013
- Manuscript Received: 19 DEC 2012
- German Research Foundation. Grant Number: LU1455/1-1
- National Natural Science Foundation of China. Grant Number: 31000475
- ADAM ;
- chicken embryo;
- gene expression
Members of the ADAM (a disintegrin and metalloprotease) family are type I transmembrane proteins involved in biological processes of proteolysis, cell adhesion, cell–matrix interaction, as well as in the intracellular signaling transduction. In the present study, expression patterns of seven members of the ADAM family were investigated at the early stages of the developing cochlea by in situ hybridization. The results show that each individual ADAM is expressed and regulated in the early developing cochlea. ADAM9, ADAM10, ADAM17, and ADAM23 are initially and widely expressed in the otic vesicle at embryonic day 2.5 (E2.5) and in the differential elements of the cochlear duct at E9, while ADAM12 is expressed in acoustic ganglion cells at E7. ADAM22 is detectable in cochlear ganglion cells as early as from E4 and in the basilar papilla from E7. Therefore, the present study extends our previous results and suggests that ADAMs also play a role in the early cochlear development.
The inner ear is an extremely complex sensory organ responsible for hearing and body balance and originates in a transient thickening of the cranial ectoderm – the otic placode, which invaginates to form the otic vesicle and then gives rise to the cochlea and the vestibular organ (Cohen & Fermin 1978; Fekete & Wu 2002; Bell et al. 2008; Sánchez-Guardado et al. 2009). Remarkably, the epithelium in the ventro-medial region of the otic vesicle forms the cochlea, while the latero-dorsal region gives rise to the vestibular organ (Torres & Giraldez 1998). Many factors, such as adhesive cadherin family (Luo et al. 2007; Yan et al. 2012), Wnt signaling molecules (Ohyama et al. 2006; Freter et al. 2008; Sienknecht & Fekete 2008), bone morphogenetic protein (BMP; Sánchez-Guardado et al. 2009; Kamaid et al. 2010; Ohyama et al. 2010), SRY-box-containing gene 2 (Sox2), Jagged1 (Jag1), paired box 2 (Pax2) and LIM homeodomain protein Islet-1 (Li et al. 2004; Neves et al. 2011, 2012), are involved in the processes of the cochlear development, in which they interact and control the processes of the cochlear maturation (Brigande et al. 2000).
The members of the ADAM (a disintegrin and metalloprotease) family belong to type I transmembrane protein and can modulate different biological processes of proteolysis, cell adhesion, cell fusion, and signaling transduction (White 2003; Blobel 2005; Reiss et al. 2005; Benarroch 2012). During embryonic development, members of the ADAM family show distinct expression patterns and are regulated spatio-temporally in different organs and tissues (Edwards et al. 2008; Alfandari et al. 2009). For example, several ADAMs, including ADAM9, ADAM10, ADAM12, ADAM13, ADAM17, ADAM22 and ADAM23, are dynamically expressed in different regions of the developing brain and spinal cord (Lin et al. 2008, 2010; Markus et al. 2011), and of the developing retina and lens (Yan et al. 2011a, 2012). Furthermore, ADAM19 is also expressed in developing brain, eye, cochlea, and digestive system (Yan et al. 2011b). Functionally, members of the ADAM family play critical roles in the spermatogenesis, fertilization, myogenesis, neurogenesis and morphogensis (Maretzky et al. 2005; Edwards et al. 2008; Alfandari et al. 2009). For example, ADAM10 plays a critical role in neurogenesis and synaptogenesis (Chen et al. 2007). Overexpression of ADAM10 can promote the cortical synaptic plasticity and influence the synaptogenesis (Bell et al. 2008). However, conditional knockout of ADAM10 in the mouse brain results in a precocious neuronal maturation and disrupts the architecture of the cortex layer (Jorissen et al. 2010). ADAM17 knockout mice die at birth because of multiple cardiovascular defects (Horiuchi et al. 2005), while overexpression of ADAM17 in the developing optic tectum induces angiogenesis by increasing blood vessel sprouting and pericyte number (Lin et al. 2011). Moreover, ADAM22-deficient mice die at early postnatal stage with ataxia and prominent hypomyelination in the peripheral nerve system (Sagane et al. 2005).
Our previous study has shown that the seven ADAMs, including ADAM9, ADAM10, ADAM12, ADAM13, ADAM17, ADAM22 and ADAM23, are expressed in the developing chicken cochlea at later stage from embryonic day (E) 11 to E18 (Yan et al. 2010). However, little is known about the expression of these ADAMs at the early stages of the developing cochlea. Therefore, to investigate whether ADAM genes are also involved in the early cochlear development, we performed in situ hybridization and analyzed the expression patterns of these seven ADAM genes in the developing cochlea from E2.5 at otic vesicle stage to E9 at cochlear duct stage. Our results showed that different ADAM is expressed in a distinct part of the otic vesicle and the cochlear duct, but with partial overlap.
Materials and methods
Fertilized eggs of white Leghorn chickens (Gallus domesticus) were incubated in a forced-draft egg incubator (BSS160, Ehret, Germany) at 37.5°C with 60% humidity. Chicken embryos were staged according to Hamburger & Hamilton (1951). The embryonic heads at E2.5 (stage 16), E3 (stage 20), E4 (stage 24), E5 (stage 26), and at E7 (stage 30) were collected and washed with phosphate-buffered saline (PBS) (13 mmol/L NaCl, 7 mmol/L Na2HPO4, 3 mmol/L NaH2PO4; pH 7.4), followed by fixation with 4% formaldehyde in ice overnight. The cochlear duct at E9 (stage 35) was directly isolated from the embryos and then fixed in formaldehyde. After being incubated in a series of 12%, 18% and 30% sucrose, the specimens were embedded with Tissue-Tec O.C.T. compound (Science Services, Munich, Germany), frozen in liquid nitrogen and stored at −80°C.
In situ hybridization
For in situ hybridization, digoxigenin (DIG)-labeled sense and antisense cRNA probes were synthesized in vitro using plasmids containing previously cloned ADAM sequences (Yan et al. 2011b, 2012) as cDNA templates according to the manufacturer's instructions (Roche, Mannheim, Germany). Sense cRNA probes were used as negative controls.
In situ hybridization on cryosections was performed according to the protocol described previously (Luo et al. 2004). In brief, after postfixation with 4% formaldehyde in PBS, cryostat sections were pretreated with proteinase K and acetic anhydride, followed by hybridized with cRNA probe at a concentration of about 1–2 ng/μL at 70°C in hybridization solution (50% formamide, 3× standard saline citrate [SSC], 1× Denhardt's solution, 250 μg/mL yeast RNA and 250 μg/mL salmon sperm DNA) overnight. After alkaline phosphatase-coupled anti-DIG Fab fragments (Roche) were added to bind to the cRNA probe at 4°C overnight, a substrate solution of nitroblue tetrazolium salt (NBT) and 5-bromo-4-chloro-3-indoyl phosphate (BCIP) was added to visualize the labeled mRNA signals.
Double fluorescent immunohistochemistry was performed according to the previously described protocol (Luo et al. 2007). In brief, after postfixation with 4% formaldehyde in Tris-buffered saline (TBS, pH 7.4), sections were preincubated with skim milk solution (5% skim milk, 0.3% Triton ×100, and 0.04% sodium azide in TBS), followed by incubation with mouse monoclonal antibody against Islet-1 (39.4D5; kindly provided by Developmental Studies Hybridoma Bank (DSHB) from University of Iowa, USA) at 4°C overnight. Then the Cy3-labelled goat anti-mouse secondary antibody (Dianova, Hamburg, Germany) was incubated for 1 h at room temperature. After the section was re-fixed with 4% formaldehyde and preincubed with skim milk solution, the mouse monoclonal antibody against Pax2 (DSHB) was added, followed by Alexa 488-labelled goat anti-mouse secondary antibody IgG (Molecular Probes, Eugene, OR, USA) at room temperature for 1 h.
The color reaction on sections of in situ hybridization and the fluorescent signals in immunohistochemistry were viewed and photographed under a microscope (BX40; Olympus, Hamburg, Germany) equipped with a digital camera (DP70; Olympus). Photographs were adjusted in contrast and brightness by the Photoshop software (Adobe, Mountain View, CA, USA).
To address the expression patterns of the ADAMs at the early developmental stages, in situ hybridization was performed from the otic vesicle at E2.5 to the cochlear duct at E9. We used a similar amount of cRNA probes of the ADAMs and the same developmental process by in situ hybridization. Expression patterns of the ADAMs were described from early to later and schematic cartoons were given to show the cutting position in the otic vesicle and the cochlear duct at different stages by lines and relative panel letters with the orientation indicated by the anterior (A), posterior (P), the medial (M), and the dorsal (D). The double fluorescent immunostaining against Pax2 and Islet-1 in the adjacent section was performed as markers to precisely identify the ADAM expressing position in the otic vesicle and the cochlear duct. Representative expression patterns of the ADAMs at E2.5 and E3 are shown in Figure 1, at E4 and E5 in Figure 2, at E7 in Figure 3, and at E9 in Figure 4. Sense cRNA probes were used as negative controls (e.g. inset in Fig. 1A for ADAM10). In general, each individual ADAM investigated here demonstrates a spatial and temporal expression pattern at the early developmental stages of the cochlea with partial overlap (Table 1).
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ADAMs expression in the otic vesicle at E2.5 and E3
The chicken inner ear originates in the otic placode beside the hindbrain and the otic vesicle specifically expresses Sox2, Jag1, and Pax2 (Li et al. 2004; Neves et al. 2011, 2012). In the sagittal sections at E2.5 and E3, the mRNAs of ADAM9 (Fig. 1A, I), ADAM10 (Fig. 1B, J) and ADAM17 (Fig. 1E, M) are strongly expressed in the otic epithelium, while ADAM23 mRNA is moderately expressed with stronger signals in the anterior and posterior parts of the otic vesicle (Fig. 1G, O). The mRNA signals of ADAM12 (Fig. 1C, K), ADAM13 (Fig. 1D, L), and ADAM22 (Fig. 1F, N) are not detectable in the otic vesicles, where Pax2 protein (green color in Fig. 1P) was expressed in the otic vesicle in the adjacent section.
ADAMs expression in the inner ear at E4 and E5
In the otic epithelium at E4 of the sagittal sections, ADAM9 (Fig. 2A), ADAM10 (Fig. 2B) and ADAM17 (Fig. 2E) are found strongly, ADAM23 moderately (Fig. 2G), but ADAM12 (Fig. 2C), ADAM13 (Fig. 2D), and ADAM22 (Fig. 2F) not detectable, where Pax2 is specifically and strongly expressed in the dorsal part of the otic vesicle (green color in Fig. 2H). Furthermore, ADAM22 and ADAM23 are expressed in the developing cochlear ganglia (cg; Fig. 2F, G), where Islet-1 is specifically expressed (red color in Fig. 2H).
At E5, the chicken inner ear undergoes important morphogenetic changes and both sensory and nonsensory elements are well recognized (Wu & Oh 1996). At this stage in the transverse sections, ADAM9 (Fig. 2I), ADAM10 (Fig. 2J) and ADAM17 (Fig. 2M) are strongly expressed by the sensory epithelial cells in the presumptive basilar papilla (bp), the endolymphatic duct (ed), the horizontal pouch (hp) and the lateral wall (lw), where Pax2 expression is specifically found in the presumptive basilar papilla and the endolymphatic duct (green color in Fig. 2P). Compared to ADAM9, ADAM10, and ADAM17, ADAM23 is moderately expressed in the presumptive basilar papilla and the endolymphatic duct, but weakly in the lateral wall (Fig. 2O). ADAM12 (Fig. 2K) and ADAM13 (Fig. 2L) signals are not detectable in the epithelium of the inner ear, but moderately in the surrounding mesenchymal cells. Although ADAM22 as well as ADAM23 belongs to the non-proteolytic members of the ADAM family and both are phylogenetically closely related (Yang et al. 2006; Yan et al. 2012), on the contrary, ADAM22 is not detectable in the epithelium of the inner ear (Fig. 2N).
Moreover, the expression of the ADAMs in the developing cochlear ganglion is also seen (Fig. 2). Remarkably, ADAM9 (Fig. 2I), ADAM10 (Fig. 2J), ADAM22 (Fig. 2N) and ADAM23 (Fig. 2O) are strongly expressed in the dorsal part of the cochlear ganglia, where Islet-1 is located (red color in Fig. 2P), although weak signals are seen in the ventral part. ADAM17 signals are also found homogenously in the cochlear ganglion (Fig. 2M).
ADAMs expression in the cochlear duct at E7
In developing embryos at E7, the sensory and non-sensory elements of the cochlea are well differentiated. In both transverse (Fig. 3A–G) and sagittal sections (Fig. 3A'–G'), the expression of the seven members of ADAMs was investigated (Fig. 3). Our results showed that in the sensory epithelium of the basilar papilla, the expression of ADAM10 (Fig. 3B, B') and ADAM17 (Fig. 3E, E') mRNAs is very strong, and of ADAM9 (Fig. 3A, A'), ADAM22 (Fig. 3F, F') and ADAM23 (Fig. 3G, G') moderate; in the lateral wall, ADAM10 (Fig. 3B, B'), ADAM17 (Fig. 3E, E') and ADAM23 (Fig. 3G, G') signals are strong, and ADAM9 is moderate (Fig. 3A, A'), but ADAM22 is not detectable (Fig. 3F, F'). In the cochlear ganglion, ADAM9 (Fig. 3A, A'), ADAM10 (Fig. 3B, B'), ADAM17 (Fig. 3E, E'), ADAM22 (Fig. 3F, F') and ADAM23 (Fig. 3G, G') signals are strongly detected, but ADAM12 very weakly (Fig. 3C, C'). Furthermore, in the vestibular ganglion (vg), ADAM17, ADAM22 and ADAM23 are also strongly expressed (Fig. 3E–G). At this stage, ADAM13 signals are not detectable in the developing cochlea (Fig. 3D, D').
ADAMs expression in the cochlear duct at E9
At E9, different types of cells in the cochlear duct can be gradually recognized, for example, hair cells and supporting cells in the basilar papilla (Cohen & Fermin 1978), where Islet-1 signal is detected strongly in the whole basilar papilla, but Pax2 partially in the up-region (Fig. 4S–U). At this stage, ADAM9 (Fig. 4A–C), ADAM10 (Fig. 4D–F), ADAM17 (Fig. 4J–L), and ADAM23 (Fig. 4P–R) are widely transcribed in the anatomical structures of the cochlear duct, for example, in the basilar papilla, in the lateral wall, in the cochlear ganglion, by the cuboidal cells and the homogene cells. The expression of ADAM12 mRNA is detected weakly in the basilar papilla, but moderately in the spindle-shaped cells (ssc) and in the cochlear ganglion (Fig. 4G–I). ADAM22 signals are present weakly in the spindle-shaped cells, but strongly in the cochlear ganglion (Fig. 4M–O). The expression of ADAM13 is not detectable at this stage (data not shown).
The expression of the ADAMs in distinct anatomical structures at the later developing chicken cochlea (from E11 onwards) has been reported previously (Yan et al. 2010, 2011b). The present work extends the previous study and investigates expressional profiles of the ADAMs at the early developing cochlea. The results show that the earliest onset of individual ADAM expression is different. For example, ADAM9, ADAM10, ADAM17, and ADAM23 are initially expressed in the otic vesicle at E2.5 (Fig. 1), but ADAM22 in the cochlear ganglion cells at E4 (Fig. 2). Generally, as the chicken embryo develops, the expression patterns of the ADAMs are dynamically changed with spatio-temporal regulation in different types of cells during cochlear development (Figs 1-4).
ADAMs expression in the developing otic vesicle
The vertebrate cochlea is derived from the otic vesicle (Lang et al. 2000; Alsina et al. 2003, 2004) and our results show that the transcription of the ADAM mRNAs, especially ADAM9, ADAM10, and ADAM17, is widely distributed in the otic epithelium at the otic vesicle stage (Figs 1, 2). The functional role of the ADAMs expressing in the otic vesicle is yet unknown. It may be speculated that the ADAMs are involved in processes of some signaling pathways, for example, the Notch signaling. Indeed, Notch-1 and its related ligands are expressed throughout the developing otic placode and control the cell fate determination (Adam et al. 1998). Of interest, ADAM10 can cleave Notch receptor (Yang et al. 2006; Edwards et al. 2008) and activate its downstream gene expression (Bland et al. 2003; LaVoie & Selkoe 2003). Conditional knockout of ADAM10 in the mouse induces the defect of the Notch signaling, causing a disturbance of the cerebral cortex structure (Jorissen et al. 2010). Furthermore, ADAM17 is also involved in ectodomain shedding of the Notch ligands and affects cell differentiation (LaVoie & Selkoe 2003; Yang et al. 2006; Edwards et al. 2008). Whether the expression of the ADAMs is actually involved in the early otic development via activation of Notch signal pathway should be further investigated.
ADAMs expression and the cochlear morphogenesis
During ontogeny, the cochlear duct emerges from the ventral otocyst and is referred to as the pars inferior, including prosensory domains that give rise to the sensory cochlea containing three structures: the vestibular saccular, the lagenar maculae and the auditory basilar papilla (Sienknecht & Fekete 2008). Previous studies have reported that members of the ADAM family are involved in the embryonic morphogenesis including the brain and the heart (Alfandari et al. 2009). For example, ADAM10 is required for the development of brain and heart in the Drosophila. Loss of ADAM10 function results in disrupted architectures of these organs (Albrecht et al. 2006; Jorissen et al. 2010). Mice lacking ADAM17 die postnataly and suffer from multiple defects in most organs including abnormal development of the skin, the eye, the digestive tract, the lung and the heart (Zhao et al. 2001; Black et al. 2003; Shi et al. 2003). Furthermore, cadherin-based cell adhesion plays an important role in the morphogenesis of the cochlea (Kelley 2003; Novince et al. 2003; Luo et al. 2007). The ADAMs are the major protease cleaving the extracellular domain of the cadherins and modulate cell–cell adhesion and signal transduction (Maretzky et al. 2005; Reiss et al. 2005; Kohutek et al. 2009; Yan et al. 2010). In this study, the ADAMs were observed to be expressed in the cochlear duct – an early stage of the cochlea (Figs 2-4), suggesting that the ADAMs may also contribute to the cochlear morphogenesis and formation in early cochlear development.
ADAMs expression in the cochlear ganglion
In the developing cochlea, neuronal precursors detach from the anterio-ventral wall of the otic epithelium, giving rise to the neurons of the acoustic-vestibular ganglion, which will innervate the various sensory patches in the developing inner ear (Torres & Giraldez 1998; Sánchez-Guardado et al. 2009). The present study demonstrates that several ADAM mRNAs are expressed by cells of the developing cochlear ganglion (Figs 2-4). Previous studies have reported that members of the ADAM family are involved in outgrowth and guidance of ganglion cells (Webber et al. 2002; McFarlane 2003; Lin et al. 2010; Yan et al. 2010, 2011b). For example, ADAM10 is important and essential for the fate determination of retinal ganglion cells (Webber et al. 2002; Yan et al. 2011b). Loss of ADAM10 function in the brain results in the wrong projection of axons from the retina to the tectum (Chen et al. 2007). ADAM17 can shed the ectodomain of neural cell adhesion molecule (NCAM), modulating neurite outgrowth (Kalus et al. 2006). Furthermore, ADAM22 and ADAM23 are also expressed in developing chicken spinal dorsal root ganglion cells (Lin et al. 2010) and play a role in cell differentiation (Sun et al. 2007). Therefore, it is of interest to investigate which function is played by ADAM expressing in the cochlear ganglion.
ADAMs expression compared in different stages
The present results show that ADAMs are expressed and regulated temporally and spatially during cochlear development. Generally, compared to the previously published data of the ADAM expression patterns in the later developing chicken cochlea, we found a comparable expression patterns in developing cochlea for most of the ADAMs between the earlier and the later stages. However, we also noted some differences. For example, the expression of ADAM9 mRNA is associated with differentiation of the sensory epithelium (Cohen & Fermin 1978); however, we found that ADAM9 is strong at early stages but weak at later stages (Yan et al. 2010). Although both ADAM10 and ADAM17 have wide expression patterns in the whole embryonic stages, the expression of ADAM10 and ADAM17 in later stages is much stronger than that in the early stages (Yan et al. 2010). Additionally, the expression of ADAM22 in the basilar papillar is only specifically observed from E7 to E9, but not in other stages (Yan et al. 2010), suggesting that ADAM22 plays an important role in a specific stage in the development of hair cells and supporting cells in the basilar papillar.
This work was supported by a grant from the German Research Foundation (DFG; LU1455/1-1) and a grant from the National Natural Science Foundation of China (31000475).
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