Co-regulation of multiple genes promote inner ear progenitors to regenerate hair cells in the mouse cochlea
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更新:2022-07-06 17:10:14
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摘要
Sensory hair cells in the inner ear are responsible for sound recognition. Damage to hair cells in adult mammals causes permanent hearing impairment because these cells cannot regenerate. By contrast, newborn mammals possess limited regenerative capacity because of the active participation of various signaling pathways. The Wnt, Notch and Atoh1 are highly sophisticated and conserved signaling pathways that control multiple cellular events necessary for the formation of sensory hair cells. All three signlaings allow resident supporting cells to regenerate hair cells in the neonatal cochlea. Foxg1 is one of the forkhead genes that are involved in morphogenesis, cell fate determination, and proliferation, and Foxg1 was previously reported to be required for morphogenesis of the mammalian inner ear. We found that Foxg1 conditional knock-down (cKD) in Sox2+ SCs and Lgr5+ progenitors at postnatal day (P)1 both led to large numbers of extra inner HCs in P7 mouse cochleae, and these extra inner HCs survived at least to P30 and had normal hair bundles and synapses. Pou4f3 and Gfi1, are orderly expressed in the process of HC differentiation and maturation. The Pou4f3 gene is an essential gene for HC formation in the cochlear development, and also is a target of ATOH1 in HCs. Gfi1 is a target of the Pou4f3 gene, and is essential for the survival of cochlear HC. Considering the possible roles of these geens in mammalian hair cell regeneration and maturation, we co-regulated these genes simultaneously in postnatal cochlear supporting cells, and explored the roles of these genes in SC-to-HC conversion and maturation of new HCs.
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