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First published online January 11, 2008
doi: 10.1242/10.1242/dev.013763

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Disruption of PDGFR-initiated PI3K activation and migration of somite derivatives leads to spina bifida

Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

^* Author for correspondence (e-mail: michelle.tallquist{at}utsouthwestern.edu)

Accepted 2 November 2007

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) results in spina bifida, but the underlying mechanism has not been identified. To elucidate the cause of this birth defect in PDGFR 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 PDGFR-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 PDGFR 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.

Key words: Spina bifida, PDGF, PI3 kinase, Cell migration, S6K1, PAK1, Mouse, Chick

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