Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes.
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.
Moon
Anne M
AM
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA. anne.moon@genetics.utah.edu
Guris
Deborah L
DL
Seo
Ji-heui
JH
Li
Leiming
L
Hammond
Jennetta
J
Talbot
Amy
A
Imamoto
Akira
A
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism; D002319:Cardiovascular System / Q000196:embryology / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000378:metabolism; D002892:Chromosomes, Human, Pair 22; D004062:DiGeorge Syndrome / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique / Q000379:methods; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005838:Genotype; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009432:Neural Crest / Q000378:metabolism; D010614:Pharynx / Q000196:embryology / Q000378:metabolism; D010641:Phenotype; D050737:Proto-Oncogene Proteins c-crk / Q000172:deficiency*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
D002630:Chemotactic Factors; C496457:Fgf8 protein, mouse; D050737:Proto-Oncogene Proteins c-crk; D017468:Receptors, Fibroblast Growth Factor; D051524:Fibroblast Growth Factor 8