Loss ofChd7function in gene-trapped reporter mice is embryonic lethal and associated with severe defects in multiple developing tissues

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Abstract

CHD7 is a novel chromodomain gene mutated in 60%-80% of humans with CHARGE syndrome, a multiple congenital anomaly condition characterized by ocular {L-End}coloboma, {L-End}heart defects, {L-End}atresia of the choanae, {L-End}retarded growth and development, {L-End}genital hypoplasia, and characteristic {L-End}ear abnormalities including deafness. Phenotypic features of CHARGE are highly variable and incompletely penetrant. To explore developmental roles of CHD7, we generated mice carrying the Chd7Gt allele from a Chd7-deficient, gene-trapped lacZ reporter ES cell line. RT-PCR of embryo RNA demonstrated significantly reduced levels of wild-type transcript in Chd7Gt/Gt embryos. Chd7Gt/Gt embryos survive only up to embryonic day 10.5 (E10.5). Chd7Gt/+ male and female mice are viable, small, and exhibit variable degrees of head-bobbing and circling, consistent with vestibular dysfunction. Paint-filling of E16.5 heterozygous inner ears revealed defects of the semicircular canals. The pattern of β-galactosidase activity in Chd7Gt/+ embryos mimics Chd7 mRNA expression in wild-type embryos, confirming the fidelity of the lacZ reporter. We observed tissue-specific β-galactosidase in the E12.5 and E14.5 Chd7Gt/+ brain, pituitary, ear, heart, and craniofacial structures, indicating survival of Chd7Gt/+ cells in CHARGE-relevant organs. These studies demonstrate the utility of Chd7Gt as a reporter-tagged loss-of-function allele for future studies exploring developmental mechanisms of Chd7 deficiency.

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