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PMID: 16399079 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes.

Developmental cell ·Vol. 10 ·No. 1 ·2006-01-00 ·Pages 71-80

Moon AM, Guris DL, Seo JH, Li L, Hammond J, Talbot A, Imamoto A

Abstract

Deletions on chromosome 22q11.21 disrupt pharyngeal and cardiac development and cause DiGeorge and related human syndromes. CRKL (CRK-Like) lies within 22q11.21, and Crkl-/- mice have phenotypic features of 22q11 deletion (del22q11) syndromes. While human FGF8 does not localize to 22q11, deficiency of Fgf8 also generates many features of del22q11 syndrome in mice. Since Fgf8 signals via receptor-type tyrosine kinases, and Crk family adaptor proteins transduce intracellular signals downstream of tyrosine kinases, we investigated whether Crkl mediates Fgf8 signaling. In addition to discovering genetic interactions between Crkl and Fgf8 during morphogenesis of structures affected in del22q11 syndrome, we found that Fgf8 induces tyrosine phosphorylation of FgfRs 1 and 2 and their binding to Crkl. Crkl is required for normal cellular responses to Fgf8, including survival and migration, Erk activation, and target gene expression. These findings provide mechanistic insight into disrupted intercellular interactions in the pathogenesis of malformations seen in del22q11 syndrome.

MeSH Terms
Animals Apoptosis Blotting, Western/methods Bone and Bones/embryology,metabolism Cardiovascular System/embryology,metabolism Cell Count/methods Cells, Cultured Chemotactic Factors/metabolism Chromosomes, Human, Pair 22 DiGeorge Syndrome/genetics,metabolism Disease Models, Animal Embryo, Mammalian Enzyme Activation Fibroblast Growth Factor 8/metabolism Fluorescent Antibody Technique/methods Gene Deletion Gene Expression Regulation, Developmental/genetics Genotype Humans Mice Mice, Knockout Models, Biological Neural Crest/metabolism Pharynx/embryology,metabolism Phenotype Proto-Oncogene Proteins c-crk/deficiency Receptors, Fibroblast Growth Factor/metabolism Signal Transduction/physiology Time Factors
Chemicals
Chemotactic Factors Fgf8 protein, mouse Proto-Oncogene Proteins c-crk Receptors, Fibroblast Growth Factor Fibroblast Growth Factor 8
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Moon Anne M
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA. [email protected]
Guris Deborah L
Seo Ji-heui
Li Leiming
Hammond Jennetta
Talbot Amy
Imamoto Akira
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Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1534-5807
DOI
10.1016/j.devcel.2005.12.003
Email
[email protected]
Published
2006-01-00
Pages
71-80
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC1780033
Subset
IM
Grants
NICHD NIH HHS · T32 HD007009 · United States
NICHD NIH HHS · R01 HD044157 · United States
NIDCR NIH HHS · R01 DE015883-02 · United States
NIDCR NIH HHS · R01 DE015883-05 · United States
NIDCR NIH HHS · R01 DE015883-01A1 · United States
NICHD NIH HHS · T32HD007009 · United States
NIDCR NIH HHS · R01 DE015883 · United States
NICHD NIH HHS · R01HD044157 · United States
NIDCR NIH HHS · R01 DE015883-04 · United States
NIDCR NIH HHS · R01 DE015883-03 · United States
NIDCR NIH HHS · R01DE015883 · United States
External Links
PubMed source DOI: 10.1016/j.devcel.2005.12.003 PMC Full Text View journal details
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