The Roles Of Disheveled Family In The Regulation Of Hair Cell Regeneration Of Zebrafish Lateral Line

The inner ear of adult mammals can't regenerate the hair cells?HCs?once they are damaged or dead,causing permanent hearing and balance dysfunction,or even the deafness and a loss of balance.In contrast,non-mammalian vertebrates like birds,amphibians and teleosts can regenerate their sensory HCs throughout their lives,in the inner ear or lateral line system.To understand why mammals fail to regenerate the HCs in damaged inner ear,studying the mechanisms underlying HC regeneration in the nonmammalian animals would be helpful for us to induce proper HCs regeneration in humans.In this project,we have chosen posterior lateral line?p LL?neuromasts of a zebrafish sim1b^{egfp Et}mutant and techniques such as live imaging,quantitative PCR,genome editing,and co-immunoprecipitation to investigate why the mutant develops normal p LL neuromast HCs but fails to regenerate nascent HCs once the p LL neuromasts are damaged by cisplatin.Our study has revealed that Sim1 b directly binds the regulatory regions of some Disheveled family members to regulate Wnt signaling activity in normal/damaged neuromasts.Sim1 b positively regulates dvl3 a expression at the m RNA level,promoting the nuclear accumulation of ?-catenin to initiate the proliferation and differentiation of HC progenitor cells in cisplatin-damaged neuromasts.On the other hand,Sim1 b negatively regulates dvl2 and dixdc1 b expression.Since the neuromast expression of sim1 b starts late after p LL is basically established,the sim1b^{egfp Et}mutant has normally developed p LL system.Knocking down either sim1 b or dvl3 a by specific anti-sense morpholino oligos increases the overall expression of dvl2 and dixdc1 b,yet the enhancement of former?3-4 fold?is more significant than that of the latter?1.5 fold?.Consequently,sim1 b morphant shows more severe HC regeneration defect than that of dvl3 a morphant.Therefore,we postulate that dvl2 and dixdc1 b may not be involved in HC regeneration of p LL neuromasts.Our study emphasizes that Sim1 b regulates p LL HC regeneration by regulating the dvl3 a to induce Wnt signaling activity required for normal HC regeneration,thus implicating a new/possible approach to clinically treat hearing/balance disorders caused by damaged inner ear HCs.