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Specific isoforms of protein kinase C are essential for prevention of folate-resistant neural tube defects by inositol.
Hum Mol Genet. 2004 Jan 01; 13(1):7-14.HM

Abstract

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 PKCbetaI and gamma for prevention of NTDs by inositol, and partial dependence on PKCzeta, whereas other PKCs (alpha, betaII delta, and epsilon) 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 PKCbetaI. Our findings reveal an essential role of specific PKC isoforms in mediating the prevention of mouse NTDs by inositol.

Authors+Show Affiliations

Cogram P
Neural Development Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Hynes A
No affiliation info available
Dunlevy LP
No affiliation info available
Greene ND
No affiliation info available
Copp AJ
No affiliation info available

MeSH

AnimalsBlotting, WesternDisease Models, AnimalEmbryo, MammalianGene Expression Regulation, EnzymologicImmunohistochemistryInositolIsoenzymesMiceMice, Mutant StrainsNeural Tube DefectsProtein Kinase C

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14613966

Citation

Cogram, Patricia, et al. "Specific Isoforms of Protein Kinase C Are Essential for Prevention of Folate-resistant Neural Tube Defects By Inositol." Human Molecular Genetics, vol. 13, no. 1, 2004, pp. 7-14.
Cogram P, Hynes A, Dunlevy LP, et al. Specific isoforms of protein kinase C are essential for prevention of folate-resistant neural tube defects by inositol. Hum Mol Genet. 2004;13(1):7-14.
Cogram, P., Hynes, A., Dunlevy, L. P., Greene, N. D., & Copp, A. J. (2004). Specific isoforms of protein kinase C are essential for prevention of folate-resistant neural tube defects by inositol. Human Molecular Genetics, 13(1), 7-14.
Cogram P, et al. Specific Isoforms of Protein Kinase C Are Essential for Prevention of Folate-resistant Neural Tube Defects By Inositol. Hum Mol Genet. 2004 Jan 1;13(1):7-14. PubMed PMID: 14613966.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Specific isoforms of protein kinase C are essential for prevention of folate-resistant neural tube defects by inositol. AU - Cogram,Patricia, AU - Hynes,Andrew, AU - Dunlevy,Louisa P E, AU - Greene,Nicholas D E, AU - Copp,Andrew J, Y1 - 2003/11/12/ PY - 2003/11/14/pubmed PY - 2004/8/11/medline PY - 2003/11/14/entrez SP - 7 EP - 14 JF - Human molecular genetics JO - Hum Mol Genet VL - 13 IS - 1 N2 - 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 PKCbetaI and gamma for prevention of NTDs by inositol, and partial dependence on PKCzeta, whereas other PKCs (alpha, betaII delta, and epsilon) 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 PKCbetaI. Our findings reveal an essential role of specific PKC isoforms in mediating the prevention of mouse NTDs by inositol. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/14613966/Specific_isoforms_of_protein_kinase_C_are_essential_for_prevention_of_folate_resistant_neural_tube_defects_by_inositol_ DB - PRIME DP - Unbound Medicine ER -