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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References
Emanuel, B.S., Burdarf, M.L. & Scambler, P.J. in Heart Development (eds. Harvey, R.P. & Rosenthal, N.) 463–478 (Academic, San Diego, 1999).
Dunham, I. et al. The DNA sequence of human chromosome 22. Nature 402, 489–495 (1999).
ten Hoeve, J., Morris, C., Heisterkamp, N. & Groffen, J. Isolation and chromosomal localization of CRKL, a human crk-like gene. Oncogene 8, 2469–2474 (1993).
La Bonne, C. & Bronner-Fraser, M. Induction and patterning of the neural crest, a stem cell-like precursor population. J. Neurobiol. 36, 175–189 (1998).
Feller, S.M. et al. Physiological signals and oncogenesis mediated through Crk family adapter proteins. J. Cell. Physiol. 177, 535–552 (1998).
Sattler, M. & Salgia, R. Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells. Leukemia 12, 637–644 (1998).
D'Amico-Martel, A. & Noden, D.M. Contributions of placodal and neural crest cells to avian cranial peripheral ganglia. Am. J. Anat. 166, 445–468 (1983).
Le Douarin, N.M. & Smith, J. Development of the peripheral nervous system from the neural crest. Annu. Rev. Cell Dev. Biol. 4, 375–404 (1988).
Shah, N.M., Marchionni, M.A., Isaacs, I., Stroobant, P. & Anderson, D.J. Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell 77, 349–360 (1994).
Dong, Z. et al. Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron 15, 585–596 (1995).
Stemple, D.L. & Anderson, D.J. Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell 71, 973–985 (1992).
Waldo, K.L., Kumiski, D. & Kirby, M.L. Cardiac neural crest is essential for the persistence rather than the formation of an arch artery. Dev. Dyn. 205, 281–292 (1996).
Kirby, M.L. in Heart Development (eds. Harvey, R.P. & Rosenthal, N.) 179–193 (Academic, San Diego, 1999).
Conway, S.J., Henderson, D.J. & Copp, A.J. Pax3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant. Development 124, 505–514 (1997).
Edelmann, L. et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum. Mol. Genet. 8, 1157–1167 (1999).
Shaikh, T.H. et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9, 489–501 (2000).
McDonald-McGinn, D.M. et al. Detection of a 22q11.2 deletion in cardiac patients suggests a risk for velopharyngeal incompetence. Pediatrics 99, E9 (1997).
Eicher, P.S. et al. Dysphagia in children with a 22q11.2 deletion: unusual pattern found on modified barium swallow. J. Pediatr. 137, 158–164 (2000).
Kimber, W.L. et al. Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse. Hum. Mol. Genet. 8, 2229–2237 (1999).
Lindsay, E.A. et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401, 379–383 (1999).
Gripp, K.W., Zackai, E.H. & Stolle, C.A. Mutations in the human TWIST gene. Hum. Mutat. 15, 150–155 (2000).
Chen, Z.F. & Behringer, R.R. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 9, 686–699 (1995).
Van Esch, H. et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406, 419–422 (2000).
Kurahashi, H. et al. Another critical region for deletion of 22q11: a study of 100 patients. Am. J. Med. Genet. 72, 180–185 (1997).
Amati, F. et al. Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome. Eur. J. Hum. Genet. 7, 903–909 (1999).
Mark, M. et al. Two rhombomeres are altered in Hoxa-1 mutant mice. Development 119, 319–338 (1993).
Chong, S.S. et al. A revision of the lissencephaly and Miller–Dieker syndrome critical regions in chromosome 17p13.3. Hum. Mol. Genet. 6, 147–155 (1997).
Begbie, J., Brunet, J.F., Rubenstein, J.L. & Graham, A. Induction of the epibranchial placodes. Development 126, 895–902 (1999).
Farrell, M., Waldo, K., Li, Y.X. & Kirby, M.L. A novel role for cardiac neural crest in heart development. Trends Cardiovasc. Med. 9, 214–220 (1999).
Conway, S.J., Henderson, D.J., Kirby, M.L., Anderson, R.H. & Copp, A.J. Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse. Cardiovasc. Res. 36, 163–173 (1997).
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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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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DOI: https://doi.org/10.1038/85855
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