Chromatin remodeling protein CHD4 regulates axon guidance of spiral ganglion neurons in developing cochlea

Abstract

AbstractThe chromodomain helicase binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler.De-novopathogenic variants ofCHD4cause Sifrim-Hitz-Weiss syndrome (SIHIWES). Patients with SIHIWES show delayed development, intellectual disability, facial dysmorphism, and hearing loss. Many cochlear cell types, including spiral ganglion neurons (SGNs), express CHD4. SGNs are the primary afferent neurons that convey sound information from the cochlea, but the function of CHD4 in SGNs is unknown. We employed the Neurog1(Ngn1) CreERT2Chd4conditional knockout animals to deleteChd4in SGNs. SGNs are classified as type I and type II neurons. SGNs lacking CHD4 showed abnormal fasciculation of type I neurons along with improper pathfinding of type II fibers. CHD4 binding to chromatin from immortalized multipotent otic progenitor-derived neurons was used to identify candidate target genes in SGNs. Gene ontology analysis of CHD4 target genes revealed cellular processes involved in axon guidance, axonal fasciculation, and ephrin receptor signaling pathway. We validated increasedEpha4transcripts in SGNs fromChd4conditional knockout cochleae. The results suggest that CHD4 attenuates the transcription of axon guidance genes to form the stereotypic pattern of SGN peripheral projections. The results implicate epigenetic changes in circuit wiring by modulating axon guidance molecule expression and provide insights into neurodevelopmental diseases.