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PMID: 19541608 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 27 ·2009-07-07 ·Pages 11270-5

Nakamura T, Gulick J, Colbert MC, Robbins J

Abstract

Mutations within the protein tyrosine phosphatase, SHP2, which is encoded by PTPN11, cause a significant proportion of Noonan syndrome (NS) cases, typically presenting with both cardiac disease and craniofacial abnormalities. Neural crest cells (NCCs) participate in both heart and skull formation, but the role of SHP2 signaling in NCC has not yet been determined. To gain insight into the role of SHP2 in NCC function, we ablated PTPN11 specifically in premigratory NCCs. SHP2-deficient NCCs initially exhibited normal migratory and proliferative patterns, but in the developing heart failed to migrate into the developing outflow tract. The embryos displayed persistent truncus arteriosus and abnormalities of the great vessels. The craniofacial deficits were even more pronounced, with large portions of the face and cranium affected, including the mandible and frontal and nasal bones. The data show that SHP2 activity in the NCC is essential for normal migration and differentiation into the diverse lineages found in the heart and skull and demonstrate the importance of NCC-based normal SHP2 activity in both heart and skull development, providing insight into the syndromic presentation characteristic of NS.

MeSH Terms
Animals Cell Differentiation Cell Movement Craniofacial Abnormalities/enzymology,pathology Down-Regulation/genetics Embryo, Mammalian/enzymology,pathology Enzyme Activation Extracellular Signal-Regulated MAP Kinases/metabolism Gene Deletion Heart/embryology Heart Defects, Congenital/enzymology,pathology Mice Mice, Knockout Neural Crest/cytology,embryology,enzymology Phenotype Phosphorylation Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism Skull/embryology,enzymology
Chemicals
Extracellular Signal-Regulated MAP Kinases Protein Tyrosine Phosphatase, Non-Receptor Type 11
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Nakamura Tomoki
Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Gulick James
Colbert Melissa C
Robbins Jeffrey
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0902230106
Published
2009-07-07
Epub
2009-00-18
Pages
11270-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2708773
Subset
IM
Grants
NHLBI NIH HHS · P01 HL059408 · United States
NHLBI NIH HHS · R01HL087862 · United States
NHLBI NIH HHS · P01HL69799 · United States
NHLBI NIH HHS · R01 HL087862 · United States
NHLBI NIH HHS · P01HL059408 · United States
NHLBI NIH HHS · P50HL07701 · United States
External Links
PubMed source DOI: 10.1073/pnas.0902230106 PMC Full Text View journal details
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