Biology subjects

Young, C. B.

Publications and source records attributed to Young, C. B..

2 recordsLinked to original sources

bioRxiv2021

Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

developmental biology↗

bioRxiv2020

A ubiquitin-based mechanism for the oligogenic inheritance of heterotaxy and heart defects

The etiology of congenital heart defects (CHDs), amongst the most common human birth defects, is poorly understood partly because of its complex genetic architecture. Here we show that two genes previously implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a single-pass transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a transmembrane ubiquitin ligase complex that catalyzes the ubiquitination and degradation of the Hedgehog pathway transducer Smoothened. Homozygous Megf8 and Mgrn1 mutations increased Smoothened abundance and elevated sensitivity to Hedgehog ligands. While mice heterozygous for loss-of-function Megf8 or Mgrn1 mutations were normal, double heterozygous embryos exhibited an incompletely penetrant syndrome of CHDs with heterotaxy. Thus, genetic interactions between components of a receptor-like ubiquitin ligase complex that tunes morphogen signaling strength can cause a birth defect syndrome inherited in an oligogenic pattern.

developmental biology↗