Abstract
The chromatin remodeling protein CHD7 is critical for proper formation of the mammalian inner ear. Humans with heterozygous pathogenic variants in CHD7 exhibit CHARGE syndrome, characterized by hearing loss and inner ear dysplasia, including abnormalities of the semicircular canals and Mondini malformations. Chd7Gt/+ heterozygous null mutant mice also exhibit dysplastic semicircular canals and hearing loss. Prior studies have demonstrated that reduced Chd7 dosage in the ear disrupts expression of genes involved in morphogenesis and neurogenesis, yet the relationships between these changes in gene expression and otic patterning are not well understood. Here, we sought to define roles for CHD7 in global regulation of gene expression and patterning in the developing mouse ear. Using single-cell multiplex qRT-PCR, we analyzed expression of 192 genes in FAC sorted cells from Pax2Cre;mT/mGFP wild type and Chd7Gt/+ mutant microdissected mouse otocysts. We found that Chd7 haploinsufficient otocysts exhibit a relative enrichment of cells adopting a neuroblast (vs. otic) transcriptional identity compared with wild type. Additionally, we uncovered disruptions in pro-sensory and pro-neurogenic gene expression with Chd7 loss, including genes encoding proteins that function in Notch signaling. Our results suggest that Chd7 is required for early cell fate decisions in the developing ear that involve highly specific aspects of otic patterning and differentiation.
Highlights
Accurate structure-function morphogenesis in the mammalian inner ear requires precisely orchestrated events controlling cellular proliferation and differentiation
Leads to changes in gene expression and otic cell patterning in single cells derived from the developing mouse embryo
Single cell analysis using multiplexed qRT-PCR of 192 genes revealed a significant shift in the distribution of otic-derived cells vs. neuroblasts in Pax2Cre+/−; Chd7Gt/+;mT/mGFP mice compared to Pax2Cre+/−; Chd7+/+; mT/mGFP littermates
Summary
Accurate structure-function morphogenesis in the mammalian inner ear requires precisely orchestrated events controlling cellular proliferation and differentiation. Over the several days of development (E9.5–E15.5 in the mouse), the otic vesicle grows and segregates into the various epithelial compartments that give rise to the semicircular canals, vestibular and auditory ganglia, and sensory epithelia such as the sensory cristae and maculae, and the organ of Corti. Coordination of this complex developmental process depends on accurate spatiotemporal control of gene expression (Fekete, 1996; Fekete et al, 1997; Fekete and Wu, 2002)
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