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

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. [Display omitted] •A cell-surface ubiquitination pathway negatively regulates Hedgehog signaling strength•This pathway promotes the ubiquitination and downregulation of Smoothened•Defects in this pathway cause limb, heart, and left-right patterning defects•Mutations in genes associated with this pathway show oligogenic inheritance Kong et al. discovered a membrane-tethered ubiquitination pathway that plays a role in the patterning of multiple tissues during development by dampening Hedgehog signaling strength. Defects in this pathway lead to disrupted left-right patterning (called heterotaxy) of the entire body plan, as well as organ-specific defects in the heart, limb, and skeleton.