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The role of Fgf8 in cardiovascular development and human congenital heart disease
Author(s) -
Moon Anne
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a34-c
Subject(s) - fgf8 , biology , haploinsufficiency , craniofacial , phenotype , signal transducing adaptor protein , genetics , cancer research , signal transduction , receptor , fibroblast growth factor , gene
The majority of patients with DiGeorge, velocardiofacial and CATCH‐22 syndromes have a deletion on chromosome 22 that results in characteristic malformations of the cardiovascular system, in addition to craniofacial defects and immune dysfunction. FGF8 is not located on human 22q11 however, Fgf8 deficiency during mouse embryogenesis produces a complex perinatal‐lethal phenotype that phenocopies human del22q11 syndromes. Furthermore, mice bearing hypomorphic alleles of Fgf8 have a variety of cardiovascular defects, suggesting that this protein has ongoing roles in multiple aspects cardiovascular development. We have investigated the tissue‐specific requirements for Fgf8 signaling in heart formation, outflow tract remodeling and pharyngeal vascular development. CRKL and related family members encode adaptor proteins that help transduce intracellular signals downstream of several classes of RTKs, including Fgf receptors. Since CRKL ( CRK‐Like ) is located within the typically deleted region in patients with del22q11 and disruption of its mouse orthologue, Crkl, causes cardiovascular, craniofacial and glandular features of del22q11 syndrome, we have also examined the role of this adaptor protein in mediating Fgf8 signaling during development of structures that are affected in humans with 22q11 deletions syndromes. Our conditional mutagenesis studies reveal that formation and patterning of the cardiovascular system is regulated by both the dosage and the source of Fgf8 in the developing pharynx. Phenotypic and biochemical data indicate that FGF8 and CRKL function in a common molecular pathway that, when disrupted by haploinsufficiency of CRKL , contributes to the pathogenesis of human del22q11 syndromes.