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

Spiral ganglion neurons (SGNs) are the primary afferent neurons that convey sound information from the cochlea, but the epigenetic changes that occur during development are unknown. We identified the chromodomain helicase binding protein 4 (CHD4) expression in SGNs. CHD4 is an ATP-dependent chromatin remodeler. We employed the Neurog1 (Ngn1) CreERT2 Chd4 conditional knockout animals to investigate Chd4 function in SGNs. SGNs are classified as type I and II neurons with different innervation patterns. 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 the ephrin receptor signaling pathway. Eph/ephrin signaling regulates various biological processes, including axon guidance. We confirmed increased Eph/ephrin transcripts in SGNs from Chd4 conditional knockout cochleae. The results implicate epigenetic changes in circuit wiring by modulating the expression of a subset of axon guidance molecules. The results also provide insights into neurodevelopmental diseases such as Sifrim-Hitz-Weiss syndrome (SIHIWES) and inform strategies for regenerating SGNs.