Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea

作者：Atkinson, Patrick J.; Dong, Yaodong; Gu, Shuping; Liu, Wenwen; Najarro, Elvis Huarcaya; Udagawa, Tomokatsu; Cheng, Alan G.^*

来源：Journal of Clinical Investigation, 2018, 128(4): 1641-1656.

DOI：10.1172/JCI97248

• NEURAL STEM-CELLS
• INNER-EAR DEVELOPMENT
• HAIR-CELLS
• BETA-CATENIN
• GENE-EXPRESSION
• IMPAIRED NEUROGENESIS
• ATOH1 EXPRESSION
• PROGENITOR CELLS
• NOTCH
• FATE

During development, Sox2 is indispensable for cell division and differentiation, yet its roles in regenerating tissues are less clear. Here, we used combinations of transgenic mouse models to reveal that Sox2 haploinsufficiency (Sox2(haplo)) increases rather than impairs cochlear regeneration in vivo. Sox2(haplo) cochleae had delayed terminal mitosis and ectopic sensory cells, yet normal auditory function. Sox2(haplo) amplified and expanded domains of damage-induced Atoh1(+) transitional cell formation in neonatal cochlea. Wnt activation via beta-catenin stabilization (beta-cateninGOF) alone failed to induce proliferation or transitional cell formation. By contrast, beta-catenin(GOF) caused proliferation when either Sox2(haplo) or damage was present, and transitional cell formation when both were present in neonatal, but not mature, cochlea. Mechanistically, Sox2(haplo) or damaged neonatal cochleae showed lower levels of Sox2 and Hes5, but not of Wnt target genes. Together, our study unveils an interplay between Sox2 and damage in directing tissue regeneration and Wnt responsiveness and thus provides a foundation for potential combinatorial therapies aimed at stimulating mammalian cochlear regeneration to reverse hearing loss in humans.

• 出版日期2018-4-2
• 单位中国医科大学