Novel Roles for CHD7 and SOX11 in CHARGE Syndrome Pathogenesis and the Developing Ear

Abstract

Tight regulation of gene expression is dependent on interactions of transcription factors and chromatin architecture. Haploinsufficiency of CHD7, which encodes a chromatin remodeling protein, is seen in individuals with CHARGE syndrome, a multiple anomaly disorder that presents with ocular colobomata, heart defects, choanal atresia, growth retardation, genital anomalies, and ear malformations. Mouse models of Chd7 deficiency have provided extensive insight into the role of this ATP-dependent chromatin remodeler in development of the central nervous system, inner ear, and olfactory system. Nevertheless, many questions remain as to the role of CHD7 in mammalian embryogenesis. In this dissertation, I address the mechanistic relationships between CHD7 and the transcription factor SOX11 in development of embryologic structures affected in CHARGE syndrome. First, I present results of a careful examination of murine craniofacial and cardiorespiratory structures in two conditional Chd7-null mouse models. Further, I show that proper expression of Chd7 is necessary for development of nasal, oropharyngeal, and tracheal structures through its function in migrating neural crest cells and developing bone. I then report on an individual with clinical features of CHARGE syndrome but no pathogenic variants within the CHD7 locus, and show that partial duplication of chromosome 2p is associated with a CHARGE-like phenotype. This study highlights the importance of clinical phenotyping and the inherent similarities between CHARGE and other syndromes. Finally, I examine the transcription factor SOX11 during vestibular morphogenesis. Using Sox11+/+ and Sox11-/- mice, I conclude that SOX11 impacts development of the lateral and posterior semicircular canals through disruption of fusion plate formation and periotic mesenchymal cell proliferation. Further, I show that Sox11 modulates Bmp4 signaling in the crista ampullaris of developing semicircular canals and may be a putative downstream effector of CHD7 in the inner ear. Together, these studies advance our understanding of CHD7 and SOX11 function during craniofacial and inner ear morphogenesis and provide new insights into genetic mechanisms in CHARGE syndrome.