The Role Of FoxGl In The Development And Survival Of Mouse Cochlear Hair Cells

Hearing loss is one of the most common sensory disorder affecting millions of adults and new born babies.Therefore,it is important to investigate the function and the detailed molecular mechanisms of the genes responsible for hearing loss.FoxG1 play an important role during the early neural development and their absence causes variety of neuro-developmental disorders.Previous studies have shown that the FoxGl knockout mice have severe deformity in the inner ear during development.However,it is hard to investigate the detailed mechanisms of FoxGl in hair cell development and survival during the postnatal period due to the embryonic lethality of FoxGl systemic knockout mice.In this study,we used Gficre FoxG1loxp/loxp mice to conditionally knockout FoxGl in hair cells;thus to explore the function and mechanism of FoxGl in hair cells development and survival during the postnatal stages.First we determined the efficiency of Gfi-Cre.The results showed that Gfi-Cre could successfully activate the expression of tdTomato and knockout the FoxGl expression particularly in hair cells.Therefore,Gfi-Cre mouse could be used as a tool to specifically knockout FoxGl expression in hair cells.The immunofluorescence results showed that extra row of hair cells has appeared in the apical and some parts of the middle turn in the cochlea of FoxGl knockout mice(P1,P7);however,hair cells in the FoxGl knockout mice gradually start to die through apoptosis as the mice aged.,The hair cell number significantly decreased at P21 and P30.Meanwhile,the RNAseq results showed that the Wnt,Notch and EGF signalling pathways appeared abnormal in hair cells of FoxGl conditional knockout(CKO)mice(P1).The significant inhibition of Notch signalling pathway might be the cause of increased hair cells number in the cochlea of FoxGl knockout mice.In addition,the inhibition of Wnt and EGF signalling pathway might affect the hair cell survival.In P21 FoxGl CKO mouse,the expression of IGF signaling pathway has been significantly inhibited.These results indicated that FoxGl and IGF signal pathway might have a co-regulatory function in the survival of hair cells.This study provides new clues and evidence for the function and mechanism of FoxGl in hair cells development and protection.