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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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 8

qPCR of Notch and Wnt target genes in damaged and Sox2-haploinsufficient cochleae.

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qPCR of Notch and Wnt target genes in damaged and Sox2-haploinsufficient...
(A) Neonatal (P1) and mature (P21) WT, Sox2CreERT2/+, Pou4f3DTR/+, and Pou4f3DTR/+ Sox2CreERT2/+ mice were treated with DT, and cochleae were collected 4 days later. (B) A significant decrease was detected in Sox2 expression levels in the neonatal Sox2CreERT2/+, Pou4f3DTR/+, and Pou4f3DTR/+ Sox2CreERT2/+ cochleae relative to levels in WT controls. (C) Only the mature Sox2CreERT2/+ and Pou4f3DTR/+ Sox2CreERT2/+ cochleae had lower Sox2 levels than those detected in control cochleae. (D) A significant decrease in the levels of the Notch target gene Hes5 was detected in Sox2CreERT2/+, Pou4f3DTR/+, and Pou4f3DTR/+ Sox2CreERT2/+ cochleae relative to levels in WT cochleae on P5. (E) When measured on P25, no significant changes in the expression levels of Hes5 were seen relative to WT cochleae. Expression levels of Sox2 and Hes5 in the mature WT cochleae were lower than levels in P5 WT cochleae. (F) Schematics depicting the extent and patterns of proliferation and Atoh1+ transitional cells under various defined conditions. Darker colors represent more robust proliferation or the formation of transitional cells. (G) Proposed model of Sox2 and damage coordination in regulating mitotic regeneration, transitional cell formation, and Wnt responsiveness. *P < 0.05 and **P < 0.01, by 1-way ANOVA with Holm-Sidak multiple comparisons test. n = 4.