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First published online August 10, 2007
doi: 10.1242/10.1242/dev.008177
1 Neural Development Unit, Institute of Child Health, University College London,
30 Guilford Street, London WC1N 1EH, UK.
2 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710,
USA.
3 Molecular Genetics and Evolution Group, Research School of Biological
Sciences, Australian National University, Canberra ACT 0200, Australia.
* Authors for correspondence (e-mails: p.ybot-gonzalez{at}ich.ucl.ac.uk; a.copp{at}ich.ucl.ac.uk)
Accepted 27 June 2007
Dorsolateral bending of the neural plate, an undifferentiated pseudostratified epithelium, is essential for neural tube closure in the mouse spinal region. If dorsolateral bending fails, spina bifida results. In the present study, we investigated the molecular signals that regulate the formation of dorsolateral hinge points (DLHPs). We show that Bmp2 expression correlates with upper spinal neurulation (in which DLHPs are absent); that Bmp2-null embryos exhibit premature, exaggerated DLHPs; and that the local release of Bmp2 inhibits neural fold bending. Therefore, Bmp signalling is necessary and sufficient to inhibit DLHPs. By contrast, the Bmp antagonist noggin is expressed dorsally in neural folds containing DLHPs, noggin-null embryos show markedly reduced dorsolateral bending and local release of noggin stimulates bending. Hence, Bmp antagonism is both necessary and sufficient to induce dorsolateral bending. The local release of Shh suppresses dorsal noggin expression, explaining the absence of DLHPs at high spinal levels, where notochordal expression of Shh is strong. DLHPs `break through' at low spinal levels, where Shh expression is weaker. Zic2 mutant embryos fail to express Bmp antagonists dorsally and lack DLHPs, developing severe spina bifida. Our findings reveal a molecular mechanism based on antagonism of Bmp signalling that underlies the regulation of DLHP formation during mouse spinal neural tube closure.
Key words: Neurulation, Morphogenesis, Neural tube defects, Noggin, Sonic hedgehog, Mouse, Zic genes
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