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

Abstract

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 humans1. 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 products3. 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.

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Figure 1: Crkol expression at E9.5 and E10.5. We determined Crkol expression by whole-mount immunohistochemistry in mouse embryos.
Figure 2: Generation of a null mutation of Crkol in mice.
Figure 3: Abnormal peripheral nervous system network in Crkol−/− embryos.
Figure 4: Abnormal cardiovascular development in Crkol−/− embryos.
Figure 5: Analysis of other tissues that depend on neural crest cells.
Figure 6: Chromosomal location of mouse Crkol.

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Acknowledgements

We thank A. Baldini for Df1 mutant samples; R. Behringer, D.H. Ledbetter, D. Mangoura, E.M. McNally, M.R. Rosner, P. Soriano and M. Tallquist for comments and critical reading of the manuscript; and H. Bigelow, S. O'Rourke, S. Bond and A. Corbin for technical assistance. The 2H3 and G3G4 monoclonal antibodies developed by T.M. Jessell and J. Dodd, and by S.J. Kaufman, respectively, were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa Department of Biological Sciences. This work was supported by an award to The University of Chicago's Division of Biological Sciences under the Research Resources Program for Medical Schools of the Howard Hughes Medical Institute and by a grant from Leukemia Research Foundation to A.I.

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Correspondence to Akira Imamoto.

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Guris, D., Fantes, J., Tara, D. et al. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet 27, 293–298 (2001). https://doi.org/10.1038/85855

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