Chromatin remodeler CHD7 is critical for cochlear morphogenesis and neurosensory patterning

• Published in: Developmental biology 2021-09, Vol.477, p.11-21
• Main Authors: Balendran, Vinodh, Skidmore, Jennifer M., Ritter, K. Elaine, Gao, Jingxia, Cimerman, Jelka, Beyer, Lisa A., Hurd, Elizabeth A., Raphael, Yehoash, Martin, Donna M.
• Format: Article
• Language: English
• Subjects: Cochlea; Development; Mouse genetics; Spiral ganglion
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2021.05.009

Epigenetic regulation of gene transcription by chromatin remodeling proteins has recently emerged as an important contributing factor in inner ear development. Pathogenic variants in CHD7, the gene encoding Chromodomain Helicase DNA binding protein 7, cause CHARGE syndrome, which presents with malformations in the developing ear. Chd7 is broadly expressed in the developing mouse otocyst and mature auditory epithelium, yet the pathogenic effects of Chd7 loss in the cochlea are not well understood. Here we characterized cochlear epithelial phenotypes in mice with deletion of Chd7 throughout the otocyst (using Foxg1Cre/+ and Pax2Cre), in the otic mesenchyme (using TCre), in hair cells (using Atoh1Cre), in developing neuroblasts (using NgnCre), or in spiral ganglion neurons (using ShhCre/+). Pan-otic deletion of Chd7 resulted in shortened cochleae with aberrant projections and axonal looping, disorganized, supernumerary hair cells at the apical turn and a narrowed epithelium with missing hair cells in the middle region. Deletion of Chd7 in the otic mesenchyme had no effect on overall cochlear morphology. Loss of Chd7 in hair cells did not disrupt their formation or organization of the auditory epithelium. Similarly, absence of Chd7 in spiral ganglion neurons had no effect on axonal projections. In contrast, deletion of Chd7 in developing neuroblasts led to smaller spiral ganglia and disorganized cochlear neurites. Together, these observations reveal dosage-, tissue-, and time-sensitive cell autonomous roles for Chd7 in cochlear elongation and cochlear neuron organization, with minimal functions for Chd7 in hair cells. These studies provide novel information about roles for Chd7 in development of auditory neurons. [Display omitted] •Chd7 is required in the mouse otocyst for cochlear elongation.•Chd7 is required in the mouse otocyst for hair cell patterning.•Chd7 is not required in peri-otic mesenchyme for inner ear morhphogenesis•Spiral ganglion neurons and cochlear hair cells are sensitive to Chd7 dosage.