Human Molecular Genetics Advance Access originally published online on November 12, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 1 7-14
DOI: 10.1093/hmg/ddh003
© 2004 Oxford University Press
Specific isoforms of protein kinase C are essential for prevention of folate-resistant neural tube defects by inositol
1Neural Development Unit, Institute of Child Health, University College London, London WC1N 1EH, UK
Received July 8, 2003; Accepted October 27, 2003
A proportion of neural tube defects (NTDs) can be prevented by maternal folic acid supplementation, although some cases are unresponsive. The curly tail mutant mouse provides a model of folate-resistant NTDs, in which defects can be prevented by inositol therapy in early pregnancy. Hence, inositol represents a possible novel adjunct therapy to prevent human NTDs. The present study investigated the molecular mechanism by which inositol prevents mouse NTDs. Activation of protein kinase C (PKC) is known to be essential, and we examined neurulation-stage embryos for PKC expression and applied PKC inhibitors to curly tail embryos developing in culture. Although all known PKC isoforms were detected in the closing neural tube, use of chemical PKC inhibitors identified a particular requirement for ‘conventional’ PKC isoforms. Peptide inhibitors offer selective inhibition of individual PKCs, and we demonstrated isoform-specific inhibition of PKC in embryonic cell cultures. Application of peptide inhibitors to neurulation-stage embryos revealed an absolute dependence on the activity of PKCßI and 
for prevention of NTDs by inositol, and partial dependence on PKC
, whereas other PKCs (
, ßII 
, and 
) were dispensable. To investigate the cellular action of inositol and PKCs in NTD prevention, we examined cell proliferation in curly tail embryos. Defective proliferation of hindgut cells is a key component of the pathogenic sequence leading to NTDs in curly tail. Hindgut cell proliferation was stimulated specifically by inositol, an effect that required activation of PKCßI. Our findings reveal an essential role of specific PKC isoforms in mediating the prevention of mouse NTDs by inositol.
* To whom correspondence should be addressed at: Neural Development Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Tel: +44 2078298893; Fax: +44 2078314366; Email: a.copp{at}ich.ucl.ac.uk
Present address: Etiologics Limited, Harwell, Oxfordshire OX11 0RD, UK.
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