Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea
Patrick J. Atkinson, … , Tomokatsu Udagawa, Alan G. Cheng
Patrick J. Atkinson, … , Tomokatsu Udagawa, Alan G. Cheng
Published March 19, 2018
Citation Information: J Clin Invest. 2018;128(4):1641-1656. https://doi.org/10.1172/JCI97248.
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Research Article Cell biology Neuroscience

Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea

Abstract

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 (Sox2haplo) increases rather than impairs cochlear regeneration in vivo. Sox2haplo cochleae had delayed terminal mitosis and ectopic sensory cells, yet normal auditory function. Sox2haplo amplified and expanded domains of damage-induced Atoh1+ transitional cell formation in neonatal cochlea. Wnt activation via β-catenin stabilization (β-cateninGOF) alone failed to induce proliferation or transitional cell formation. By contrast, β-cateninGOF caused proliferation when either Sox2haplo or damage was present, and transitional cell formation when both were present in neonatal, but not mature, cochlea. Mechanistically, Sox2haplo 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.

Authors

Patrick J. Atkinson, Yaodong Dong, Shuping Gu, Wenwen Liu, Elvis Huarcaya Najarro, Tomokatsu Udagawa, Alan G. Cheng

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Figure 4

β-Catenin stabilization and Sox2 haploinsufficiency coordinate to increase mitotic regeneration in the damaged neonatal mouse cochlea.

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β-Catenin stabilization and Sox2 haploinsufficiency coordinate to increa...
(A) Pou4f3DTR/+ Fgfr3-iCre Ctnnb1fl(ex3)/+ and Pou4f3DTR/+ Sox2CreERT2/+ Ctnnb1fl(ex3)/+ pups were injected with DT on P1, tamoxifen on P2, and EdU daily (P3–P5), and cochleae were collected on P5. (B) Schematic depicting the domains of Fgfr3 and Sox2 expression in the neonatal mouse cochlea. (C–E) Confocal images of cochleae from P5 Pou4f3DTR/+ Fgfr3-iCre Ctnnb1fl(ex3)/+ mice showing EdU+myosin 7a+ hair cells (arrowhead) and EdU+Sox2+ supporting cells (chevrons) in the apical turn, but not in the middle or basal turn. Note that many EdU+Sox2– cells resided outside the sensory epithelium. (F–H) In Pou4f3DTR/+ Sox2CreERT2/+ Ctnnb1fl(ex3)/+ cochlea, there was a robust increase in the number of EdU+myosin 7a+ hair cells (arrowheads) and Sox2+ supporting cells (chevrons) in the apical turn. As with Pou4f3DTR/+ Sox2CreERT2/+ cochlea, EdU+ supporting cells were noted in the middle turns and occasionally in the basal turns. Many EdU+Sox2– cells outside the sensory epithelium were also noted. (I) Quantification of EdU+myosin 7a+ hair cells and EdU+Sox2+ supporting cells in Pou4f3DTR/+, Pou4f3DTR/+ Fgfr3-iCre Ctnnb1fl(ex3)/+, and Pou4f3DTR/+ Sox2CreERT2/+ Ctnnb1fl(ex3)/+ cochleae. Data represent the mean ± SD. *P < 0.05 and ***P < 0.001, by 1-way ANOVA with Holm-Sidak multiple comparisons test. n = 3–5. Scale bar: 20 μm.