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 5

β-Catenin stabilization and Sox2 haploinsufficiency coordinate to increase transitional cell formation 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)/+ mice were injected with DT on P1, followed by tamoxifen administration on P2, and cochleae were examined on P4. (B, D, and F) As with Pou4f3DTR/+ cochlea, some transitional cells (Atoh1+Gfi1+Sox2+myosin 7a+, arrows) were detected in the apical and middle turns of the Pou4f3DTR/+ Fgfr3-iCre Ctnnb1fl(ex3)/+ cochlea. Some Atoh1+Gfi1+Sox2+ (myosin 7a–) cells (arrowheads), which were rarely seen in the Pou4f3DTR/+ cochlea, were also noted in the supporting cell layer of apical and middle turns. Some myosin 7a+Atoh1–Gfi1– hair cells (chevrons) were also observed in all 3 turns and were presumed to be surviving hair cells. (C, E, and G) In the Pou4f3DTR/+ Sox2CreERT2/+ Ctnnb1fl(ex3)/+ cochlea, a marked increase in transitional cells was observed in all 3 turns. (H) Quantification revealed that significantly more transitional cells were detected in all 3 turns in the Pou4f3DTR/+ Sox2CreERT2/+ Ctnnb1fl(ex3)/+ cochleae than in either Pou4f3DTR/+ or Pou4f3DTR/+ Fgfr3-iCre Ctnnb1fl(ex3)/+ cochleae. Data represent the mean ± SD. **P < 0.01 and ***P < 0.001, by 1-way ANOVA with Holm-Sidak multiple comparisons test. n = 3. Scale bar: 20 μm.