Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome

Heterozygous deletions within human chromosome 22q11 are the genetic basis of DiGeorge/velocardiofacial syndrome (DGS/VCFS), the most common deletion syndrome (1 in 4,000 live births) in humans(1). CRKL maps within the common deletion region for DCS/VCFS (ref. 2) and encodes an SH2-SH3-SH3 adapter p rotein closely related to the Crk gene products(3). Here we report that mic e homozygous for a targeted null mutation at the CrkL locus (gene symbol Cr kol for mice) exhibit defects in multiple cranial and cardiac neural crest derivatives including the cranial ganglia, aortic arch arteries, cardiac ou tflow tract, thymus, parathyroid glands and craniofacial structures, We sho w that the migration and early expansion of neural crest cells is unaffecte d in Crkol(-/-) embryos, These results therefore indicate an essential stag e- and tissue-specific role for Crkol in the function, differentiation, and /or survival of neural crest cells during development. The similarity betwe en the Crkol(-/-) phenotype and the clinical manifestations of DCS/VCFS imp licate defects in CRKL-mediated signaling pathways as part of the molecular mechanism underlying this syndrome.