Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea
Patrick J. Atkinson, Yaodong Dong, Shuping Gu, Wenwen Liu, Elvis Huarcaya Najarro, Tomokatsu Udagawa, Alan G. Cheng
Patrick J. Atkinson, Yaodong Dong, Shuping Gu, Wenwen Liu, Elvis Huarcaya Najarro, Tomokatsu Udagawa, Alan G. Cheng
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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 2

Reduced Sox2 levels enhance and expand the domain of proliferation in the damaged neonatal mouse cochlea.

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Reduced Sox2 levels enhance and expand the domain of proliferation in th...
(A) Schematic of hair cell ablation in neonatal cochlea. Briefly, Pou4f3DTR/+ and Pou4f3DTR/+ Sox2CreERT2/+ mice were injected with DT on P1 to induce hair cell loss, followed by administration of EdU (P3–P5), and cochleae were examined on P5. (B–D) No EdU+ hair cells or supporting cells were found in any of the 3 WT cochlear turns. (E–G) In the Pou4f3DTR/+ cochlea, after DT-induced hair cell damage, EdU+myosin 7a+ hair cells (arrowhead) and some EdU+Sox2+ supporting cells (chevrons) were observed in the apical turn, but not in the basal or middle turns. (H–J) In Pou4f3DTR/+ Sox2CreERT2/+ cochlea, there was robust EdU labeling of both myosin 7a+ hair cells (arrowheads) and Sox2+ supporting cells (chevrons) in the apical turn. EdU+Sox2+ supporting cells were also found in the middle turn. (K) Quantification of EdU+myosin 7a+ hair cells and myosin 7a–Sox2+ supporting cells per cochlear turn. Data represent the mean ± SD. *P < 0.05 and ***P < 0.001, by 1-way ANOVA with Holm-Sidak multiple comparisons test. n = 5–6. Scale bar: 20 μm.