Sox10 promotes the survival of cochlear progenitors during the establishment of the organ of Corti. Dev Biol

GIGA-Neurosciences, University of Liege, Belgium.
Developmental Biology (Impact Factor: 3.55). 09/2009; 335(2):327-39. DOI: 10.1016/j.ydbio.2009.09.007
Source: PubMed


Transcription factors of the SoxE family are critical players that underlie various embryological processes. However, little is known about their function during inner ear development. Here, we show that Sox10 is initially expressed throughout the otic vesicle epithelium and becomes later restricted to supporting cells as cell differentiation proceeds in the organ of Corti. Morphological analyses of Sox10 mutant mice reveal a significant shortening of the cochlear duct likely resulting from the progressive depletion of cochlear progenitors. While Sox10 appears dispensable for the differentiation and patterning of the inner ear prosensory progenitors, our data support a critical role for this transcription factor in the promotion of their survival. We provide genetic evidences that Sox10, in a concentration-dependant manner, could play a role in the regulation of Jagged1, a gene known to be important for inner ear prosensory development. Together, our results demonstrate that Sox10 regulates the biology of early cochlear progenitors during inner ear development, but, in contrast to neural crest-derived cells, this transcription factor is dispensable for their differentiation. Evidence also suggests that this effect occurs via the activation of the Jagged1 gene.

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    • "Sox9 and Sox10 are known to be expressed in the otic placode and the otic vesicle in frog and chick [17-20]. In mice, SOX9 is also expressed in the otic placode and otic vesicle and controls invagination [21], and both SOX9 and SOX10 have been found in the mouse cochlear duct epithelium [22-26]. Interestingly, in mice, Sox9 and Sox10 are downregulated before or upon hair cell differentiation, whereas Sox2 is downregulated gradually, although all three Sox genes remain expressed in the underlying supporting cells in the OC [8,22,23]. "
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    ABSTRACT: Hearing depends on correct functioning of the cochlear hair cells, and their innervation by spiral ganglion neurons. Most of the insight into the embryological and molecular development of this sensory system has been derived from animal studies. In contrast, little is known about the molecular expression patterns and dynamics of signaling molecules during normal fetal development of the human cochlea. In this study, we investigated the onset of hair cell differentiation and innervation in the human fetal cochlea at various stages of development. At 10 weeks of gestation, we observed a prosensory domain expressing SOX2 and SOX9/SOX10 within the cochlear duct epithelium. In this domain, hair cell differentiation was consistently present from 12 weeks, coinciding with downregulation of SOX9/SOX10, to be followed several weeks later by downregulation of SOX2. Outgrowing neurites from spiral ganglion neurons were found penetrating into the cochlear duct epithelium prior to hair cell differentiation, and directly targeted the hair cells as they developed. Ubiquitous Peripherin expression by spiral ganglion neurons gradually diminished and became restricted to the type II spiral ganglion neurons by 18 weeks. At 20 weeks, when the onset of human hearing is thought to take place, the expression profiles in hair cells and spiral ganglion neurons matched the expression patterns of the adult mammalian cochleae. Our study provides new insights into the fetal development of the human cochlea, contributing to our understanding of deafness and to the development of new therapeutic strategies to restore hearing.
    Neural Development 10/2013; 8(1):20. DOI:10.1186/1749-8104-8-20 · 3.45 Impact Factor
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    • "Last, because in the normal cochlear development HC differentiation precedes SC differentiation, and newly generated HCs can induce additional SCs [24], we propose that in our studies emergence of new HCs occurs earlier than new SCs as well. However, we currently lack the precise marker to define the SC fate and Sox10 is turned on in the entire otic vesicle epithelium [34], which prevents us from determining the onset of the new SC formation. "
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    ABSTRACT: During mouse inner ear development, Notch1 signaling first specifies sensory progenitors, and subsequently controls progenitors to further differentiate into either hair cells (HCs) or supporting cells (SCs). Overactivation of NICD (Notch1 intracellular domain) at early embryonic stages leads to ectopic HC formation. However, it remains unclear whether such an effect can be elicited at later embryonic or postnatal stages, which has important implications in mouse HC regeneration by reactivation of Notch1 signaling. We performed comprehensive in vivo inducible overactivation of NICD at various developmental stages. In CAG(CreER+); Rosa26-NICD(loxp/+) mice, tamoxifen treatment at embryonic day 10.5 (E10.5) generated ectopic HCs in the non-sensory regions in both utricle and cochlea, whereas ectopic HCs only appeared in the utricle when tamoxifen was given at E13. When tamoxifen was injected at postnatal day 0 (P0) and P1, no ectopic HCs were observed in either utricle or cochlea. Interestingly, Notch1 signaling induced new HCs in a non-cell-autonomous manner, because the new HCs did not express NICD. Adjacent to the new HCs were cells expressing the SC marker Sox10 (either NICD+ or NICD-negative). Our data demonstrate that the developmental stage determines responsiveness of embryonic otic precursors and neonatal non-sensory epithelial cells to NICD overactivation, and that Notch 1 signaling in the wild type, postnatal inner ear is not sufficient for generating new HCs. Thus, our genetic mouse model is suitable to test additional pathways that could synergistically interact with Notch1 pathway to produce HCs at postnatal ages.
    PLoS ONE 03/2012; 7(3):e34123. DOI:10.1371/journal.pone.0034123 · 3.23 Impact Factor
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    • "We observed that Venus fluorescence was not limited to classical NC lineage tissue, but was also observed in non-NC tissues, including the otic vesicle. This is consistent with previous studies in which in situ hybridization revealed endogenous Sox10 expression in otic vesicle cells [28,29], which are the primitive state of the vestibulocochlear nucleus (cranial nerve VIII). In the facial area of the E11.5 d embryo, aggregated green cells were observed among scattered Venus-positive cells (Figure 1B). "
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    ABSTRACT: While several mouse strains have recently been developed for tracing neural crest or oligodendrocyte lineages, each strain has inherent limitations. The connection between human SOX10 mutations and neural crest cell pathogenesis led us to focus on the Sox10 gene, which is critical for neural crest development. We generated Sox10-Venus BAC transgenic mice to monitor Sox10 expression in both normal development and in pathological processes. Tissue fluorescence distinguished neural crest progeny cells and oligodendrocytes in the Sox10-Venus mouse embryo. Immunohistochemical analysis confirmed that Venus expression was restricted to cells expressing endogenous Sox10. Time-lapse imaging of various tissues in Sox10-Venus mice demonstrated that Venus expression could be visualized at the single-cell level in vivo due to the intense, focused Venus fluorescence. In the adult Sox10-Venus mouse, several types of mature and immature oligodendrocytes along with Schwann cells were clearly labeled with Venus, both before and after spinal cord injury. In the newly-developed Sox10-Venus transgenic mouse, Venus fluorescence faithfully mirrors endogenous Sox10 expression and allows for in vivo imaging of live cells at the single-cell level. This Sox10-Venus mouse will thus be a useful tool for studying neural crest cells or oligodendrocytes, both in development and in pathological processes.
    Molecular Brain 10/2010; 3(1):31. DOI:10.1186/1756-6606-3-31 · 4.90 Impact Factor
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