A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development.

A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development. Dev Cell. 2020 Sep 19;: Authors: Kong JH, Young CB, Pusapati GV, Patel CB, Ho S, Krishnan A, Lin JI, Devine W, Moreau de Bellaing A, Athni TS, Aravind L, Gunn TM, Lo CW, Rohatgi R Abstract The etiology of congenital heart defects (CHDs), which are among the most common human birth defects, is poorly understood because of its complex genetic architecture. Here, we show that two genes implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a receptor-like 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 can arise from biochemical mechanisms that calibrate morphogen signaling strength, a conclusion broadly relevant for the many human diseases in which oligogenic inheritance is emerging as a mechanism for heritability. PMID: 32966817 [PubMed - as supplied by publisher]
Source: Developmental Cell - Category: Cytology Authors: Tags: Dev Cell Source Type: research