LMO7 deficiency reveals the significance of the cuticular plate for hearing function

Abstract

Sensory hair cells, the mechanoreceptors of the auditory and vestibular system, harbor two specialized organelles, the hair bundle and the cuticular plate. Both subcellular structures have adapted to facilitate the remarkable sensitivity and speed of hair cell mechanotransduction. While the mechanosensory hair bundle is extensively studied, the molecules and mechanisms mediating the development and function of the cuticular plate are poorly understood. The cuticular plate is believed to provide a rigid foundation for stereociliar pivot movements, but specifics about its function, especially the significance of its integrity for long-term maintenance of hair cell mechanotransduction, are not known. In this study, we describe the discovery of a hair cell protein called LIM only protein 7 (LMO7). In the hair cell, LMO7 is specifically localized in the cuticular plate. Lmo7 KO mice suffer multiple deficiencies in the cuticular plate, including reduced filamentous actin density and abnormal length and distribution of stereociliar rootlets. In addition to the cuticular plate defects, older Lmo7 KO mice develop abnormalities in inner hair cell stereocilia. Together, these defects affect cochlear tuning and sensitivity and give rise to late-onset progressive hearing loss. Author contributionsTTD, JBD, EW, SP and JBS performed the experiments. TTD, JBD and JBS analyzed the data. EPR, WX and JSO provided material and support. TTD and JBS wrote the manuscript.

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

“…Supplemental File 1 contained the entire list of enriched genes. The OHC-enriched genes included genes that are recognized to be highly expressed in adult OHCs, such as Myo7a, Ocm, Prestin (Slc26a5), Ikzf2, Espn, Tmc1, Cib2, Lhfpl5, Lmo7, Lbh, and Sri (Chessum et al, 2018;Du et al, 2019;Giese et al, 2017;Liu et al, 2014;Ranum et al, 2019;Xiong et al, 2012;Zheng et al, 2000). As expected, previously identified IHC-specific genes such as Slc7a14 (blue arrows in Figure 6-figure supplement 1A)…”

“…We first compared gene profiles between wild-type OHCs at P30 (P30_WT OHCs) and wild-type SCs at P60 (P60_WT SCs), and we identified 1324 and 2344 genes enriched respectively in adult OHCs and adult SCs (Figure 6-figure supplement 1A); Supplemental File 1 contained the entire list of enriched genes. The OHC-enriched genes included genes that are recognized to be highly expressed in adult OHCs, such as Myo7a , Ocm , Prestin (Slc26a5) , Ikzf2 , Espn , Tmc1 , Cib2 , Lhfpl5 , Lmo7 , Lbh , and Sri (Chessum et al, 2018; Du et al, 2019; Giese et al, 2017; Liu et al, 2014; Ranum et al, 2019; Xiong et al, 2012; Zheng et al, 2000). As expected, previously identified IHC-specific genes such as Slc7a14 (blue arrows in Figure 6-figure supplement 1A) were either not detected or minimally detected in our picked Tdtomato+ OHCs (Liu et al, 2014); by contrast, previously known pan-SC markers, such as Sox2 and Sox10 , and two recently identified DC-specific genes, Bace2 and Ceacam16 , were included among the SC-enriched genes (Li et al, 2018; Ranum et al, 2019).…”

“…These genes were enriched in adult wild-type OHCs (Supplemental File 1). Notably, Lmo7 mutant mice have been reported to show abnormalities in HC stereocilia (Du et al, 2019). GO analysis revealed that the genes expressed at higher levels in P30_WT OHCs were enriched in transport and lipid transport (Figure 6-figure supplement 5C).…”

Rbm24a Is Necessary for Hair Cell Development Through Regulating mRNA Stability in Zebrafish

“…Smpx protein has been localized at the actin-based cuticular plate, a specialized structure at the apical surface of hair cells (Ghilardi et al, 2020). The cuticular plate is important for stabilizing the stereocilia, and its deficits could lead to stereocilia abnormalities (Pollock and McDermott, 2015;Du et al, 2019). Our present data suggest that Rbm24a might affect stereocilia development through regulating the stability of smpx mRNA.…”

Chicken Auditory Supporting Cells Express Interferon Response Genes during Regeneration towards Nascent Sensory Hair CellsIn Vivo

“…For example, LMO7 is 1160-fold higher expressed (FDR = 2.7 × 10 −53 ) in mature hair cells compared to the 96-hour, new hair cell group. LMO7 is localized to the cuticular plate in mice and is responsible for F-actin and stereocilia organization (Du et al, 2019). Since cuticular plate development parallels stereocilia development (Duckert and Rubel, 1990), we argue that LMO7 is a late-onset gene required only after hair cell commitment and differentiation has occurred around 72-96 hours post-sisomicin.…”