CHD7-dependent regulation of migration and morphogenesis

The National Institute of Child Health and Human Development awarded Magee-Womens Research Institute and Foundation $462,538 for a Project Grant (CFDA 93.865) on June 1, 2026.

The funded research investigates CHD7-dependent regulation of cell migration and morphogenesis in kidney development, using a cross-species approach combining the nematode C. elegans and the frog X. laevis as model systems. The work focuses on how loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) contribute to renal anomalies observed in CHARGE syndrome and Kallmann syndrome, with particular emphasis on extracellular matrix dysfunction and TGFβ pathway regulation during embryonic kidney development.

The recipient is Magee-Womens Research Institute and Foundation, a Pittsburgh-based nonprofit research organization focused on women's health, reproductive biology, and maternal-fetal medicine. The award covers performance at Pittsburgh, PA 15213 with a period of performance from June 1, 2026 through May 31, 2028. The project grant is categorized as Assistance Type: Project Grant and operates under the Child Health and Human Development Extramural Research program.

Abstract

Charge syndrome is a congenital, multisystemic, developmental disorder caused by loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 (CHD7). Charge is classified as a neurocristopathy, with defects in neural crest cell (NCC) specification, migration and differentiation contributing to many of its characteristic developmental anomalies. However, patients also frequently present with renal, genital, and cardiac defects, suggesting that CHD7 functions more broadly in embryogenesis beyond NCC derivatives. CHD7 is also mutated in kallmann syndrome, a genetic disorder characterized by hypogonadism and anosmia, and occasionally, kidney abnormalities. Although renal anomalies are common in charge, kallmann, and related disorders, the molecular mechanisms by which CHD7 and its downstream effectors contribute to kidney pathogenesis remain largely undefined. Kidney development relies on coordinated cell movements and ECM remodeling; disruptions in this process can lead to structural abnormalities of the kidney and urinary tract, as seen in charge patients. In this proposal, we use a cross-species approach to reveal new insights into CHD7's role in kidney development. We use the nematode c. Elegans as a discovery tool for genes and downstream pathways regulated by CHD-7 and the frog x. Laevis to study the impact on the developing kidney. We recently observed that CHD-7 mutant worms have a highly penetrant defect in somatic gonad morphogenesis. Like the vertebrate kidney, the worm somatic gonad is shaped by complex interactions between the underlying ECM and the migrating tissue. We previously showed that CHD7 regulates tgfβ pathways affecting critical developmental processes through ECM modulation in both worm and frog models. In aim 1, we explore how ECM dysfunction promotes CHD7-associated pathologies by characterization of the impacts of CHD7 loss on both worm somatic gonad and x. Laevis pronephros morphogenesis and associated changes in BM composition in both species. In aim 2, we follow up on putative downstream targets of CHD-7. Our analyses revealed that CHD-7 binds to the regulatory region of MIR-34, a microrna whose loss phenocopies CHD-7 deficiency in gonad migration, longevity, and dauer formation in worms. In humans, members of the MIR-34/449 family are located within two genomic regions deleted in charge-related syndromes, suggesting that this mirna family is an evolutionarily conserved downstream target of CHD7, a hypothesis we test in aim 2.