Deletion of C1ql1 Causes Hearing Loss and Abnormal Auditory Nerve Fibers in the Mouse Cochlea

Abstract

Complement C1q Like 1 (C1QL1), a secreted component of C1Q-related protein, is known to play an important role in synaptic maturation, regulation, and maintenance in the central nervous system. C1ql1 is expressed in adult cochlear inner and outer hair cells (IHCs and OHCs) with preferential expression in OHCs. We generated C1ql1 null mice to examine the role of C1QL1 in the auditory periphery. C1ql1-null mice exhibited progressive hearing loss with elevated thresholds of auditory brainstem response and distortion product otoacoustic emission. Confocal microscopy showed that the number of nerve fibers innervating both IHCs and OHCs was significantly reduced. However, spiral ganglion neurons appeared to be normal under electron microscopy. IHC development and survival were not affected by deletion of C1ql1. Voltage-clamp recording and immunocytochmistry combined with confocal microscopy showed C1ql1-null IHCs showed no significant reduction of pre-synaptic proteins and synaptic vesicle release. This is in contrast to significant OHC loss in the KO mice. Our study suggests that C1ql1 is essential for development of hair cell innervation and OHC survival. But maturation of presynaptic machinery in IHCs does not depend on C1QL1.

Astrocyte ensheathment of calyx‐forming axons of the auditory brainstem precedes accelerated expression of myelin genes and myelination by oligodendrocytes

“…The neurofilament antibody was made against purified bovine Neurofliament‐Heavy and recognizes a 200‐ to 220‐kDa band in western blots (manufacturer's data sheet). Immunostaining with the anti‐neurofilament antibody showed the same pattern of labeling as in previous reports (Qi et al., 2021). The Mog antibody was made against rat cerebellar glycoproteins and binds to a discontinuous epitope present on the extracellular immunoglobulin V‐like domain of Mog (manufacturer's data sheet).…”

Generation and initial characterization of mice lacking full‐length BAI3 (ADGRB3) expression

“…It is possible that Adgrb3 ∆7/∆7 mutants might exhibit abnormalities in behaviours that were not examined in the current study. For example, mice lacking the ADGRB3 ligand, C1QL3, 15 display altered circadian activity, 53 and mice lacking C1QL1 15 exhibit impaired cerebellar motor learning 16 and reduced auditory brainstem response during audiometric testing 54 . Furthermore, we cannot exclude the possibility that the residual bands detected by Western blotting in Adgrb3 ∆7/∆7 mice might represent functional ADGRB3 protein isoforms.…”

“…For example, mice lacking the ADGRB3 ligand, C1QL3, 15 display altered circadian activity, 53 and mice lacking C1QL1 15 exhibit impaired cerebellar motor learning 16 and reduced auditory brainstem response during audiometric testing. 54 Furthermore, we cannot exclude the possibility that the residual bands detected by Western blotting in Adgrb3 Δ7/Δ7 mice might represent functional ADGRB3 protein isoforms. Shorter N-terminal truncated forms of ADGRB1 were recently shown to arise from usage of an alternative promoter in intron 17 of ADGRB1.…”

Macrophages Are Dispensable for Postnatal Pruning of the Cochlear Ribbon Synapses

“…C4 is a schizophrenia risk gene in humans and also mediates synapse elimination during postnatal development in mice (Sekar et al, 2016 ). However, the involvements of C1q and C1ql1 in postnatal pruning of cochlear ribbon synapses have been excluded in knockout mouse models (Calton et al, 2014 ; Qi et al, 2021 ). While C4 is also expressed in the postnatal cochlea and is induced by Slc26a4 deficiency, whether it plays a role in cochlear synapse pruning remains to be determined (Jabba et al, 2006 ).…”