Bhavana Iyengar
Pronouns: she/her
Research Mentor(s): Donna Martin
Research Mentor School/College/Department: Pediatrics-Genetics / Medicine
Program: UROP
Session: Session 2 (10:00am – 10:50am)
Authors: Jelka Cimerman, Bhavana Iyengar, Donna M. Martin
Abstract
Background: SOX11 and SOX4, both SoxC transcription factors in the SRY-related high-mobility-group (HMG) box family, have been implicated in inner ear morphogenesis. SOX11 is a genetic target of CHD7, an ATP-dependent chromatin remodeler and key regulator of neurogenesis. Haploinsufficiency of CHD7 results in CHARGE syndrome, which presents with hearing loss and balance impairment due to inner ear dysplasia. Pathogenic variants in SOX11-related Coffin-Siris syndrome exhibit phenotypic overlap with CHARGE syndrome associated with growth delays and ear malformations. The specific mechanisms by which loss of CHD7 or SOX11 affects ear development are not known. Objective: We aimed to explore potential molecular genetic pathways of Sox11 and Chd7 in the developing mouse inner ear. Design/Methods: Dosage of Sox4, Sox11, and Chd7 (Sox11-/-, Pax2Cre;Sox11flox/flox, Pax2Cre;Sox4flox/+; Sox11flox/flox, Pax2Cre; Sox4flox/flox, and Chd7Gt/+;Sox11+/-) were examined for embryonic inner ear morphological abnormalities using paint-filling and histological analysis. Inner ear gene expression changes were assessed using qRT-PCR, immunofluorescence and in situ hybridization, while cell proliferation and apoptosis were examined by BrdU incorporation and anti-Caspase, respectively. Results: Semicircular canals and endolymphatic duct abnormalities were observed in Sox11-/-, Pax2Cre;Sox11flox/flox, Pax2Cre;Sox4flox/+; Sox11flox/flox, and Chd7Gt/+;Sox11+/- embryos. In contrast, Pax2Cre; Sox4flox/flox inner ears exhibited mild enlargement of the common crus and endolymphatic duct. Sox11-/- mutants exhibited delayed formation of the canal fusion plate despite normal laminin expression and increased cell proliferation in the surrounding mesenchyme but no evidence of aberrant cell death. Chd7 expression was unchanged in Sox11-/- mutant otocysts at E10.5. In contrast, expression of Sox11 throughout the E10.5 Chd7Gt/Gt otocyst was highly reduced. Bmp4 expression in the presumptive lateral crista ampullaris was reduced in Sox11-/- inner ears compared to Sox11+/+ otocyst at E11.5.
