Journal Article

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

Imamoto, Akira, Druker, Brian J., Fantes, Judith, Tara, David, Guris, Deborah L.

2001

Overview

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 DGS/VCFS (ref. 2 ) and encodes an SH2-SH3-SH3 adapter protein closely related to the Crk gene products 3 . Here we report that mice homozygous for a targeted null mutation at the CrkL locus (gene symbol Crkol for mice) exhibit defects in multiple cranial and cardiac neural crest derivatives including the cranial ganglia, aortic arch arteries, cardiac outflow tract, thymus, parathyroid glands and craniofacial structures. We show that the migration and early expansion of neural crest cells is unaffected in Crkol −/− embryos. These results therefore indicate an essential stage- and tissue-specific role for Crkol in the function, differentiation, and/or survival of neural crest cells during development. The similarity between the Crkol −/− phenotype and the clinical manifestations of DGS/VCFS implicate defects in CRKL-mediated signaling pathways as part of the molecular mechanism underlying this syndrome.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adapter proteins / Adaptor Proteins, Signal Transducing / Agriculture / Animal Genetics and Genomics / Animals / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Births / Cancer Research / chromosome 22 / Chromosome Deletion / Chromosomes, Human, Pair 22 - genetics / Complications and side effects / CRKL gene / Crkol gene / Diagnosis / DiGeorge Syndrome - embryology / DiGeorge Syndrome - genetics / Disease Models, Animal / Embryos / Gene Expression Regulation, Developmental / Gene Function / Gene mutations / Genetics / Growth factors / Heterozygote / Human Genetics / Humans / Immunodeficiencies / Immunodeficiencies. Immunoglobulinopathies / Immunological deficiency syndromes / Immunopathology / In Situ Hybridization, Fluorescence / Kinases / letter / Medical sciences / Mice / Mice, Knockout / Mutation / Nuclear Proteins - deficiency / Nuclear Proteins - genetics / Oncology / Phenotype / Physical Chromosome Mapping / Physiological aspects / Publishing / Risk factors / velocardiofacial syndrome