A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development.
Dev Cell
; 55(4): 432-449.e12, 2020 11 23.
Article
en En
| MEDLINE
| ID: mdl-32966817
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Proteínas Hedgehog
/
Ubiquitinación
/
Corazón
Límite:
Animals
Idioma:
En
Revista:
Dev Cell
Asunto de la revista:
EMBRIOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos