FCHSD2 is required for stereocilia maintenance in mouse cochlear hair cells

Abstract

Stereocilia are F-actin-based protrusions on the apical surface of inner ear hair cells, and are indispensable for hearing and balancing perception. Stereocilia of each hair cell are organized into rows of increasing heights, forming a staircase-like pattern. The development and maintenance of stereocilia are tightly regulated, and deficits in this process lead to stereocilia disorganization and hearing loss. Previously, we showed that F-BAR protein FCHSD2 is localized along the stereocilia of cochlear hair cells, and could cooperate with CDC42 to regulate F-actin polymerization and cell protrusion formation in cultured COS-7 cells. In the present work, Fchsd2 knockout mice were established to investigate the role of FCHSD2 in hearing. Our data show that stereocilia maintenance is severely affected in cochlear hair cells of Fchsd2 knockout mice, which leads to progressive hearing loss. Moreover, Fchsd2 knockout mice show increased acoustic vulnerability. Noise exposure causes robust stereocilia degeneration as well as enhanced hearing threshold elevation in Fchsd2 knockout mice. Lastly, Fchsd2/Cdc42 double knockout mice show more severe stereocilia deficits and hearing loss, suggesting that FCHSD2 and CDC42 may cooperatively regulate stereocilia maintenance.

Endosomal actin branching, fission and receptor recycling require FCHSD2 recruitment by MICAL-L1

“…FCHSD2 has been implicated in receptor recycling (Xiao et al, 2018;Xiao & Schmid, 2020) and Nwk localizes to recycling endosomes (Rodal et al, 2011). Indeed, consistent with roles for FCHSD2 in both endocytic function and actin regulation, FCHSD2 regulates ciliogenesis and knock-out mice display acoustic vulnerability and hearing loss (Wang et al, 2022;Zhai et al, 2022a). Moreover, Nwk activates WASP to promote ARP2/3-dependent actin filament assembly (Stanishneva-Konovalova et al, 2016), and similarly FCHSD2 stimulates ARP2/3 on flat membranes (Almeida-Souza et al, 2018).…”