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Notch signaling regulates Akap12 expression and primary cilia length during renal tubule morphogenesis
- Source :
- FASEB J
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- Alagille syndrome patients present with loss of function mutations in either JAG1 or NOTCH2. About 40-50% of patients have kidney abnormalities, with multi-cystic, dysplastic kidneys being one of the more frequent kidney defects. Additionally, gain-of-function mutations in NOTCH2 are associated with cystic kidneys in Hajdu-Cheney syndrome patients. Conditional inactivation of Notch1, Notch2, or RBPJ within the nephrogenic lineage impairs nephrogenesis and produces proximal tubule cysts in mice. How perturbations in Notch signaling cause renal tubular cysts remains unclear. Here we have determined that inhibition of Notch signaling in the kidney increases Akap12 expression. Ectopic expression of Akap12 in renal epithelia results in abnormally long primary cilia similar to those observed in Notch-signal-deficiency. Both loss of Notch signaling and elevated Akap12 expression disrupt the ability of renal epithelial cells to form spherical structures with a single lumen when grown embedded in matrix. We conclude that Notch signaling regulates Akap12 expression to ensure normal primary cilia length and renal epithelial morphogenesis, and suggest that diseases associated with defective Notch signaling, such as Alagille syndrome, maybe mechanistically related to ciliopathies.Translational StatementThe current study examines how a reduction in Notch signaling results in abnormal renal tubule formation, as occurs in Alagille Syndrome patients with mutations in JAG1 or NOTCH2. The finding that reduced Notch signaling results in abnormally long cilia is suggestive that some of the clinical manifestations in Alagille Syndrome, such as small cystic kidneys, may originate due to defective cilia function. Linking Notch to primary cilia also opens up the possibility that coinheritance of mutations in ciliopathy genes along with a mutation in JAG1 or NOTCH2 may enhance the severity of the clinical phenotypes such as cystic kidney disease and may explain the variable occurrence and onset of kidney disease among Alagille Syndrome patients.
- Subjects :
- 0301 basic medicine
Male
JAG1
030232 urology & nephrology
Notch signaling pathway
Kidney development
A Kinase Anchor Proteins
Cell Cycle Proteins
Biology
Biochemistry
Renal tubule morphogenesis
Article
Cystic kidney disease
03 medical and health sciences
Mice
0302 clinical medicine
Alagille syndrome
Genetics
medicine
Morphogenesis
Animals
Cilia
Receptor, Notch2
Molecular Biology
030304 developmental biology
Genes, Dominant
Cystic kidney
Mice, Knockout
0303 health sciences
Cilium
Nuclear Proteins
medicine.disease
Cell biology
Mice, Inbred C57BL
Ciliopathy
030104 developmental biology
Kidney Tubules
Gene Expression Regulation
Ectopic expression
Female
030217 neurology & neurosurgery
Biotechnology
Transcription Factors
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- FASEB J
- Accession number :
- edsair.doi.dedup.....d229e2c661b932250088994e2423bfb9
- Full Text :
- https://doi.org/10.1101/760181