Abstract
Primary auditory neurons (PANs) connect cochlear sensory hair cells in the mammalian inner ear to cochlear nucleus neurons in the brainstem. PANs develop from neuroblasts delaminated from the proneurosensory domain of the otocyst and keep maturing until the onset of hearing after birth. There are two types of PANs: type I, which innervate the inner hair cells (IHCs), and type II, which innervate the outer hair cells (OHCs). Glial cells surrounding these neurons originate from neural crest cells and migrate to the spiral ganglion. Several transcription factors are known to regulate the development and differentiation of PANs. Here we systematically examined the spatiotemporal expression of five transcription factors: Sox2, Sox10, Gata3, Mafb, and Prox1 from early delamination at embryonic day (E) 10.5 to adult. We found that Sox2 and Sox10 were initially expressed in the proneurosensory cells in the otocyst (E10.5). By E12.75 both Sox2 and Sox10 were downregulated in the developing PANs; however, Sox2 expression transiently increased in the neurons around birth. Furthermore, both Sox2 and Sox10 continued to be expressed in spiral ganglion glial cells. We also show that Gata3 and Prox1 were first expressed in all developing neurons, followed by a decrease in expression of Gata3 and Mafb in type I PANs and Prox1 in type II PANs as they matured. Moreover, we describe two subtypes of type II neurons based on Peripherin expression. These results suggest that Sox2, Gata3 and Prox1 play a role during neurogenesis as well as maturation of the PANs.
MeSH terms
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Animals
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Cell Nucleus / metabolism
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Cochlea / embryology*
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Cochlea / growth & development
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Cochlea / metabolism
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GATA3 Transcription Factor / biosynthesis*
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GATA3 Transcription Factor / genetics
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Gene Expression Regulation, Developmental*
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Gene Knock-In Techniques
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Genes, Reporter
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Gestational Age
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Homeodomain Proteins / biosynthesis*
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Homeodomain Proteins / genetics
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MafB Transcription Factor / biosynthesis
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MafB Transcription Factor / genetics
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Mice
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Nerve Tissue Proteins / biosynthesis*
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Nerve Tissue Proteins / genetics
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Neural Crest / metabolism
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Neural Stem Cells / metabolism
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Neurogenesis* / genetics
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Neuroglia / metabolism
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Peripherins / biosynthesis
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Peripherins / genetics
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Recombinant Fusion Proteins / biosynthesis
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SOXB1 Transcription Factors / biosynthesis*
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SOXB1 Transcription Factors / genetics
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SOXE Transcription Factors / biosynthesis
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SOXE Transcription Factors / genetics
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Sensory Receptor Cells / classification
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Sensory Receptor Cells / metabolism*
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Spiral Ganglion / embryology*
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Spiral Ganglion / metabolism
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Tumor Suppressor Proteins / biosynthesis*
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Tumor Suppressor Proteins / genetics
Substances
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Homeodomain Proteins
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MafB Transcription Factor
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Mafb protein, mouse
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Nerve Tissue Proteins
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Peripherins
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Prph protein, mouse
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Recombinant Fusion Proteins
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SOXB1 Transcription Factors
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SOXE Transcription Factors
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Sox10 protein, mouse
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Sox2 protein, mouse
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Tumor Suppressor Proteins
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prospero-related homeobox 1 protein
Grants and funding
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This research was undertaken thanks in part to funding provided to the University of Toronto Medicine by Design initiative, by the Canada First Research Excellence Fund (AD), Koerner Foundation (AD), a Harry Barberian grant (TN), Uehara Memorial Foundation (TN), Japan Society for the Promotion of Science KAKENHI Grant number 15H06911 (KN), 16K20293 (KN), Leave a Nest grant IKEDA SCIENTIFIC award (KN) and the Sunnybrook Hearing Regeneration Initiative.