The role of Sox2 in neurosensory development is not yet fully understood. Using mice with conditional Islet1-cre mediated deletion of Sox2, we explored the function of Sox2 in neurosensory development in a model with limited cell type diversification, the inner ear. In Sox2 conditional mutants, neurons initially appear to form normally, whereas late- differentiating neurons of the cochlear apex never form. Variable numbers of hair cells differentiate in the utricle, saccule, and cochlear base but sensory epithelium formation is completely absent in the apex and all three cristae of the semicircular canal ampullae. Hair cells differentiate only in sensory epithelia known or proposed to have a lineage relationship of neurons and hair cells. All initially formed neurons lacking hair cell targets die by apoptosis days after they project toward non-existing epithelia. Therefore, late neuronal development depends directly on Sox2 for differentiation and on the survival of hair cells, possibly derived from common neurosensory precursors.

Department of Biology University of Iowa Iowa City IA USA

Faculty of Science Charles University Prague Czechia

Institute of Biotechnology CAS Prague Czechia

Institute of Experimental Medicine CAS Prague Czechia

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Kondoh H. & Lovell-Badge R. Sox2: Biology and Role in Development and Disease. 3–15 (Elsevier, 2016).

Reiprich S. & Wegner M. From CNS stem cells to neurons and glia: Sox for everyone. Cell Tissue Res 359, 111–124 (2015). PubMed

Telley L. et al.. Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex. Science 351, 1443–1446 (2016). PubMed

Fritzsch B., Jahan I., Pan N. & Elliott K. L. Evolving gene regulatory networks into cellular networks guiding adaptive behavior: an outline how single cells could have evolved into a centralized neurosensory system. Cell Tissue Res 359, 295–313 (2015). PubMed PMC

Fritzsch B., Pan N., Jahan I. & Elliott K. L. Inner ear development: building a spiral ganglion and an organ of Corti out of unspecified ectoderm. Cell Tissue Res 368, 7–24 (2015). PubMed PMC

Dabdoub A., Fritzsch B., Popper A. N. & Fay R. R. The Primary Auditory Neurons of the Mammalian Cochlea. Vol. 52 (Springer, 2016).

Ma Q., Anderson D. J. & Fritzsch B. Neurogenin 1 null mutant ears develop fewer, morphologically normal hair cells in smaller sensory epithelia devoid of innervation. J Assoc Res Otolaryngol 1, 129–143 (2000). PubMed PMC

Matei V. et al.. Smaller inner ear sensory epithelia in Neurog 1 null mice are related to earlier hair cell cycle exit. Developmental Dynamics 234, 633–650 (2005). PubMed PMC

Raft S. & Groves A. K. Segregating neural and mechanosensory fates in the developing ear: patterning, signaling, and transcriptional control. Cell Tissue Res, 359, 315–32 (2014). PubMed PMC

Yang T., Kersigo J., Jahan I., Pan N. & Fritzsch B. The molecular basis of making spiral ganglion neurons and connecting them to hair cells of the organ of Corti. Hear Res 278, 21–33 (2011). PubMed PMC

Mak A. C., Szeto I. Y., Fritzsch B. & Cheah K. S. Differential and overlapping expression pattern of SOX2 and SOX9 in inner ear development. Gene Expr Patterns 9, 444–453 (2009). PubMed PMC

Gu R. et al.. Lineage tracing of Sox2− expressing progenitor cells in the mouse inner ear reveals a broad contribution to non-sensory tissues and insights into the origin of the organ of Corti. Developmental Biology 414, 72–84 (2016). PubMed PMC

Neves J., Uchikawa M., Bigas A. & Giraldez F. The prosensory function of Sox2 in the chicken inner ear relies on the direct regulation of Atoh1. PLoS one 7, e30871 (2012). PubMed PMC

Jahan I., Pan N., Kersigo J. & Fritzsch B. Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea. PloS one 5, e11661 (2010). PubMed PMC

Evsen L., Sugahara S., Uchikawa M., Kondoh H. & Wu D. K. Progression of neurogenesis in the inner ear requires inhibition of Sox2 transcription by Neurogenin1 and Neurod1. J Neurosci 33, 3879–3890 (2013). PubMed PMC

Huang M. et al.. Diverse expression patterns of LIM-homeodomain transcription factors (LIM-HDs) in mammalian inner ear development. Developmental Dynamics 237, 3305–3312 (2008). PubMed PMC

Radde-Gallwitz K. et al.. Expression of Islet1 marks the sensory and neuronal lineages in the mammalian inner ear. J Comp Neurol 477, 412–421 (2004). PubMed PMC

Yang L. et al.. Isl1Cre reveals a common Bmp pathway in heart and limb development. Development 133, 1575–1585 (2006). PubMed PMC

Pauley S., Lai E. & Fritzsch B. Foxg1 is required for morphogenesis and histogenesis of the mammalian inner ear. Developmental Dynamics 235, 2470–2482 (2006). PubMed PMC

Chang W., Brigande J. V., Fekete D. M. & Wu D. K. The development of semicircular canals in the inner ear: role of FGFs in sensory cristae. Development 131, 4201–4211 (2004). PubMed

Kiernan A. E. et al.. Sox2 is required for sensory organ development in the mammalian inner ear. Nature 434, 1031–1035 (2005). PubMed

Pan N. et al.. Conditional deletion of Atoh1 using Pax2-Cre results in viable mice without differentiated cochlear hair cells that have lost most of the organ of Corti. Hear Res 275, 66–80 (2011). PubMed PMC

Pauley S. et al.. Expression and function of FGF10 in mammalian inner ear development. Developmental dynamics 227, 203–215 (2003). PubMed PMC

Ma Q., Chen Z., del Barco Barrantes I., de la Pompa J. L. & Anderson D. J. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron 20, 469–482 (1998). PubMed

Puligilla C., Dabdoub A., Brenowitz S. D. & Kelley M. W. Sox2 induces neuronal formation in the developing mammalian cochlea. J Neurosci 30, 714–722 (2010). PubMed PMC

Bouchard M., de Caprona D., Busslinger M., Xu P. & Fritzsch B. Pax2 and Pax8 cooperate in mouse inner ear morphogenesis and innervation. BMC Dev Biol 10, 89 (2010). PubMed PMC

Fritzsch B., Kersigo J., Yang T., Jahan I. & Pan N. In The Primary Auditory Neurons of the Mammalian Cochlea 49–84 (Springer: New York, 2016).

Rubel E. W. & Fritzsch B. Auditory system development: primary auditory neurons and their targets. Annu Rev Neurosci 25, 51–101 (2002). PubMed

Mao Y., Reiprich S., Wegner M. & Fritzsch B. Targeted deletion of Sox10 by Wnt1-cre defects neuronal migration and projection in the mouse inner ear. PloS one 9, e94580 (2014). PubMed PMC

Fritzsch B., Dillard M., Lavado A., Harvey N. L. & Jahan I. Canal cristae growth and fiber extension to the outer hair cells of the mouse ear require Prox1 activity. PloS one 5, e9377 (2010). PubMed PMC

Kersigo J. & Fritzsch B. Inner ear hair cells deteriorate in mice engineered to have no or diminished innervation. Front Aging Neurosci 7, 33 (2015). PubMed PMC

Fritzsch B., Silos-Santiago I., Bianchi L. M. & Farinas I. In Seminars in cell & developmental biology. Vol. 8, 277–284 (Elsevier, 1997). PubMed

Jahan I., Pan N., Kersigo J. & Fritzsch B. Beyond generalized hair cells: molecular cues for hair cell types. Hear Res 297, 30–41 (2013). PubMed PMC

Sheykholeslami K. et al.. A new mutation of the Atoh1 gene in mice with normal life span allows analysis of inner ear and cerebellar phenotype in aging. PloS one 8, e79791 (2013). PubMed PMC

Jahan I., Pan N., Elliott K. L. & Fritzsch B. The quest for restoring hearing: understanding ear development more completely. Bioessays 37, 1016–1027 (2015). PubMed PMC

Jahan I., Pan N., Kersigo J. & Fritzsch B. Neurog1 can partially substitute for Atoh1 function in hair cell differentiation and maintenance during organ of Corti development. Development 142, 2810–2821 (2015). PubMed PMC

Ahmed M. et al.. Eya1-six1 interaction is sufficient to induce hair cell fate in the cochlea by activating atoh1 expression in cooperation with sox2. Dev Cell 22, 377–390 (2012). PubMed PMC

Pan N. et al.. A novel Atoh1 “self-terminating” mouse model reveals the necessity of proper Atoh1 level and duration for hair cell differentiation and viability. PloS one 7, e30358 (2012). PubMed PMC

Dabdoub A. et al.. Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea. Proceedings of the National Academy of Sciences 105, 18396–18401 (2008). PubMed PMC

Kempfle J. S., Turban J. L. & Edge A. S. Sox2 in the differentiation of cochlear progenitor cells. Sci Rep 6, 23293 (2016). PubMed PMC

Reiprich S. et al.. In GLIA. Vol 57, Issue S13, S26–S171 (2009).

Cheah K. S. E. & Xu P.-X. In Sox2 (ed Robin Lovell-Badge) 263–280 (Academic Press, 2016).

Kim W.-Y. et al.. NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development. Development 128, 417–426 (2001). PubMed PMC

Goodrich L. V. In The Primary Auditory Neurons of the Mammalian Cochlea 11–48 (Springer, 2016).

Fritzsch B. et al.. Development and evolution of inner ear sensory epithelia and their innervation. Journal of neurobiology 53, 143–156 (2002). PubMed PMC

Farinas I. et al.. Spatial shaping of cochlear innervation by temporally regulated neurotrophin expression. J Neurosci 21, 6170–6180 (2001). PubMed PMC

Ruben R. J. Development of the inner ear of the mouse: a radioautographic study of terminal mitoses. Acta oto-laryngologica Suppl 220, 221 (1967). PubMed

Coate T. M. & Kelley M. W. In Seminars in cell & developmental biology. Vol. 24, 460–469 (Elsevier, 2013). PubMed PMC

Gnedeva K. & Hudspeth A. SoxC transcription factors are essential for the development of the inner ear. Proceedings of the National Academy of Sciences 112, 14066–14071 (2015). PubMed PMC

Mulvaney J. & Dabdoub A. Atoh1, an essential transcription factor in neurogenesis and intestinal and inner ear development: function, regulation, and context dependency. J Assoc Res Otolaryngol 13, 281–293 (2012). PubMed PMC

Shroyer N. F. et al.. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132, 2478–2488 (2007). PubMed

Chumak T. et al.. Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice. Mol Neurobiol 53, 2368–83 (2015). PubMed

Kopecky B. J., Duncan J. S., Elliott K. L. & Fritzsch B. Three-dimensional reconstructions from optical sections of thick mouse inner ears using confocal microscopy. J Microsc 248, 292–298 (2012). PubMed PMC

Preibisch S., Saalfeld S. & Tomancak P. Globally optimal stitching of tiled 3D microscopic image acquisitions. Bioinformatics 25, 1463–1465 (2009). PubMed PMC

Fritzsch B., Duncan J. S., Kersigo J., Gray B. & Elliott K. L. In Auditory and Vestibular Research: Methods and Protocols. (ed Sokolowski B.) 221–246 (Springer, 2016).

Simmons D., Duncan J., de Caprona D. C. & Fritzsch B. In Auditory and vestibular efferents 187–216 (Springer: New York, 2011).

Duncan J. S., Elliott K. L., Kersigo J., Gray B. & Fritzsch B. Combining Whole-Mount In Situ Hybridization with Neuronal Tracing and Immunohistochemistry. In Situ Hybridization Methods 339–352 (2015).

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