RESUMO
Rer1 is a retrieval receptor for endoplasmic reticulum (ER) retention of various ER membrane proteins and unassembled or immature components of membrane protein complexes. However, its physiological functions during mammalian development remain unclear. This study aimed to investigate the role of Rer1-mediated quality control system in mammalian development. We show that Rer1 is required for the sufficient cell surface expression and activity of γ-secretase complex, which modulates Notch signaling during mouse cerebral cortex development. When Rer1 was depleted in the mouse cerebral cortex, the number of neural stem cells decreased significantly, and malformation of the cerebral cortex was observed. Rer1 loss reduced γ-secretase activity and downregulated Notch signaling in the developing cerebral cortex. In Rer1-deficient cells, a subpopulation of γ-secretase complexes and components was transported to and degraded in lysosomes, thereby significantly reducing the amount of γ-secretase complex on the cell surface. These results suggest that Rer1 maintains Notch signaling by maintaining sufficient expression of the γ-secretase complex on the cell surface and regulating neural stem cell maintenance during cerebral cortex development.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Córtex Cerebral/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Glicoproteínas de Membrana/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Adaptadoras de Transporte Vesicular , Animais , Comportamento Animal , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Córtex Cerebral/metabolismo , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 1/genética , Modelos Animais de Doenças , Feminino , Humanos , Lisossomos/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Células-Tronco Neurais , Receptores Citoplasmáticos e Nucleares/genética , Receptores Notch/metabolismoRESUMO
Caroli's disease and Caroli's syndrome are rare congenital disorders characterized by non-obstructive cystic dilatation of the intrahepatic bile ducts. These disorders are often associated with autosomal recessive polycystic kidney disease. A young woman at 11 weeks of gestation was referred to our hospital for proper management of Caroli's disease during pregnancy. Magnetic resonance imaging and laboratory tests revealed Caroli's disease with chronic renal failure caused by polycystic kidney disease. She received diet control, erythropoietin and prophylactic oral antibiotics. Her pregnancy course was uneventful, and she gave birth at 37 weeks of gestation. Thereafter, her renal function gradually worsened. Hemodialysis was begun 5 years after parturition. Though the courses of pregnancies complicated by Caroli's disease or Caroli's syndrome are variable and can include life-threatening conditions, uneventful outcomes can be expected if careful management prevents biliary and renal infection.