Ubiquitin Tunes Hedgehog in Matters of the Heart
| Autor: | Saikat Mukhopadhyay, Sandii Constable |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Body Patterning
Digit number Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Ubiquitin Hedgehog Proteins Molecular Biology book Hedgehog 030304 developmental biology 0303 health sciences biology Ubiquitination Developmental cell Heart Oligogenic Inheritance Cell Biology Hedgehog signaling pathway biology.protein book.journal Neuroscience 030217 neurology & neurosurgery Signal Transduction Developmental Biology |
| Zdroj: | Dev Cell |
| ISSN: | 1534-5807 |
| Popis: | The etiology of congenital heart defects (CHDs), amongst 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. |
| Databáze: | OpenAIRE |
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