Disruption of PDGFRalpha-initiated PI3K activation and migration of somite derivatives leads to spina bifida
| Autor: | Gregory S. Olsen, Michelle D. Tallquist, Elizabeth A. Pickett |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Mesoderm
congenital hereditary and neonatal diseases and abnormalities Receptor Platelet-Derived Growth Factor alpha Biology Piperazines Article Mice Phosphatidylinositol 3-Kinases Phosphoserine Growth factor receptor Cell Movement medicine Animals Molecular Biology Spinal Dysraphism Spina bifida Neural tube Cell migration medicine.disease Embryo Mammalian Spine Cell biology nervous system diseases Enzyme Activation Somite medicine.anatomical_structure Imatinib mesylate Cartilage Phenotype Pyrimidines Somites Focal Adhesion Protein-Tyrosine Kinases Immunology Benzamides Mutation biology.protein Imatinib Mesylate ras Proteins Mitogen-Activated Protein Kinases Chickens Chondrogenesis Proto-Oncogene Proteins c-akt Platelet-derived growth factor receptor Developmental Biology Signal Transduction |
| Zdroj: | Development (Cambridge, England). 135(3) |
| ISSN: | 0950-1991 |
| Popis: | Spina bifida, or failure of the vertebrae to close at the midline, is a common congenital malformation in humans that is often synonymous with neural tube defects (NTDs). However, it is likely that other etiologies exist. Genetic disruption of platelet-derived growth factor receptor (PDGFR) αresults in spina bifida, but the underlying mechanism has not been identified. To elucidate the cause of this birth defect in PDGFRα mutant embryos, we examined the developmental processes involved in vertebrae formation. Exposure of chick embryos to the PDGFR inhibitor imatinib mesylate resulted in spina bifida in the absence of NTDs. We next examined embryos with a tissue-specific deletion of the receptor. We found that loss of the receptor from chondrocytes did not recapitulate the spina bifida phenotype. By contrast, loss of the receptor from all sclerotome and dermatome derivatives or disruption of PDGFRα-driven phosphatidyl-inositol 3′ kinase (PI3K) activity resulted in spina bifida. Furthermore, we identified a migration defect in the sclerotome as the cause of the abnormal vertebral development. We found that primary cells from these mice exhibited defects in PAK1 activation and paxillin localization. Taken together, these results indicate that PDGFRα downstream effectors, especially PI3K, are essential for cell migration of a somite-derived dorsal mesenchyme and disruption of receptor signaling in these cells leads to spina bifida. |
| Databáze: | OpenAIRE |
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