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bioRxiv · 10.1101/2024.01.31.578202

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

Kim, J.·Martinez, E.·Qiu, J.·Ni, J. Z.·Kwan, K.
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Abstract

Spiral ganglion neurons (SGNs) are the primary afferent neurons that convey auditory information from the cochlea to the central nervous system. Pathogenic variants of human chromodomain helicase DNA-binding protein 4 (CHD4) cause Sifrim-Hitz-Weiss (SIHIWES) syndrome, a neurodevelopmental disorder associated with hearing loss. Here, we identified expression of CHD4, an ATP-dependent chromatin remodeler, in developing SGNs and proceeded to delete Chd4 in mice. Auditory brainstem recordings showed that animals lacking Chd4 in SGNs exhibit hearing loss. SGNs are classified as type I and type II neurons, which display distinct peripheral innervation patterns. Notably, loss of CHD4 resulted in abnormal fasciculation of type I neurons and improper pathfinding of type II fibers. To uncover the underlying molecular mechanisms, we mapped genome-wide CHD4 chromatin occupancy in immortalized multipotent otic progenitor (iMOP)-derived neurons. Gene ontology analysis of CHD4 target genes revealed pathways governing axon guidance, axonal fasciculation, and ephrin receptor signaling. In vivo, we observed upregulation of specific Eph/ephrin genes in SGNs from Chd4-conditional knockout cochleae. Together, these results demonstrate that CHD4 modulates chromatin at cis-regulatory elements to repress a subset of axon guidance molecules during development. The coordinated regulation of multiple guidance cues is essential for establishing precise neural circuitry in the cochlea. Our findings reveal a critical role for CHD4-dependent epigenetic regulation in neural circuit wiring and offer a translational framework for strategies to regenerate SGNs.

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Kim, J., Martinez, E., Qiu, J., Ni, J. Z., Kwan, K.. 2024-02-01. Chromatin remodeling protein CHD4 regulates axon guidance of spiral ganglion neurons in developing cochlea. https://doi.org/10.1101/2024.01.31.578202

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