BAIAP2L2 is required for the maintenance of mechanotransducing stereocilia of cochlear hair cells

Abstract

Stereocilia are actin-based cell protrusions of inner ear hair cells that play an essential role in mechano-electrical transduction (MET). Stereocilia are organized into several rows of increasing heights with the MET protein complex localized at the tips of shorter row stereocilia. At the tips of shorter row mechanotransducing stereocilia also resides a so-called "row 2 protein complex" whose dysfunction causes degeneration of the mechanotransducing stereocilia. In the present work, we show that BAIAP2L2 is localized at the tips of shorter row stereocilia in neonatal and adult mouse cochlear hair cells. Baiap2l2 inactivation causes degeneration of the mechanotransducing stereocilia, which eventually leads to profound hearing loss in mice of either sex. Consistently, electrophysiology and FM 1-43FX dye uptake results confirm that MET currents are compromised in Baiap2l2 knockout mice.Moreover, BAIAP2L2 binds to known row 2 complex components EPS8L2, TWF2, and CAPZB2, and the stereociliary tip localization of CAPZB2 is dependent on functional BAIAP2L2. Interestingly, BAIAP2L2 also binds to CIB2, a known MET complex component, and the stereociliary tip localization of BAIAP2L2 is abolished in Cib2 knockout mice. In conclusion, our present data suggest that BAIAP2L2 is a row 2 complex component, and is required for the maintenance of mechanotransducing stereocilia. Meanwhile, specific MET components such as CIB2 might play a direct role in stereocilia maintenance through binding to BAIAP2L2.

BAIAP2L2 Inactivation Does Not Affect Stereocilia Development or Maintenance in Vestibular Hair Cells

“…To explore the possible reason why loss of BAIAP2L2 does not affect VHC stereocilia or vestibular function, we tried to examine the stereociliary localization of other row 2 complex components in VHCs by performing whole-mount immunostaining and confocal microscopy. Here, we focused on CAPZB2 since its stereociliary tip localization in cochlear hair cells has been shown to depend on BAIAP2L2 ( Yan et al, 2021 ). The results show that in the utricle of P30 control mice, CAPZB2 immunoreactivity is localized at the tips of shorter-row stereocilia as reported previously ( Avenarius et al, 2017 ; Figure 4A , top panel).…”

“…BAIAP2L2 is a recently identified row 2 complex component that localizes at the tips of shorter-row mechanotransducing stereocilia in cochlear hair cells ( Carlton et al, 2021 ; Yan et al, 2021 ). BAIAP2L2 inactivation results in mechanotransducing stereocilia degeneration in cochlear hair cells, and leads to profound hearing loss ( Carlton et al, 2021 ; Yan et al, 2021 ). In the present work, we show that BAIAP2L2 is also localized at the tips of shorter-row stereocilia in VHCs.…”

“…Animal experiments were approved by the Animal Ethics Committee of Shandong University School of Life Sciences (Permit Number: SYDWLL-2020-31) and performed accordingly. Baiap2l2 and Lhfpl5 knockout mice were established and maintained as previously reported ( Xiong et al, 2012 ; Yan et al, 2021 ).…”

“…Evidences suggest that deficiency of row 2 complex components leads to degeneration of the mechanotransducing stereocilia ( Furness et al, 2013 ; Fang et al, 2015 ). Recently, we and others identified BAI1-associated protein 2-like 2 (BAIAP2L2, also known as Pinkbar) as a new component of row 2 complex ( Carlton et al, 2021 ; Yan et al, 2021 ). BAIAP2L2 inactivation causes degeneration of the mechanotransducing stereocilia in cochlear hair cells, and leads to profound hearing loss in mice ( Carlton et al, 2021 ; Yan et al, 2021 ).…”

“…Recently, we and others identified BAI1-associated protein 2-like 2 (BAIAP2L2, also known as Pinkbar) as a new component of row 2 complex ( Carlton et al, 2021 ; Yan et al, 2021 ). BAIAP2L2 inactivation causes degeneration of the mechanotransducing stereocilia in cochlear hair cells, and leads to profound hearing loss in mice ( Carlton et al, 2021 ; Yan et al, 2021 ). Furthermore, the stereociliary tip localization of the known row 2 complex component, CAPZB2, is abolished in Baiap2l2 knockout mice, suggesting that BAIAP2L2 is indispensable for the formation of row 2 complex in cochlear hair cells ( Yan et al, 2021 ).…”