SCID dogs: similar transplant potential but distinct intra-uterine growth defects and premature replicative senescence compared with SCID mice.
We have previously described DNA-dependent protein kinase (DNA-PKcs) mutations in horses and dogs that result in deficits in V(D)J recombination, DNA repair, and SCID. In this paper, we document substantial developmental growth defects in DNA-PKcs-deficient dogs that are not apparent in SCID mice. Fibroblast cell strains derived from either fetal or adult SCID dogs proliferate poorly in culture and undergo premature replicative senescence, somewhat reminiscent of cells derived from Ku-deficient mice. A limited number of animals have been immune reconstituted (by bone marrow transplantation) so that they can be maintained in a normal environment for long periods. Several of these animals have developed conditions associated with premature ageing at 2-3 years of age, roughly 20% of their expected lifespan. These conditions include intestinal malabsorption and primary neural cell neoplasia. These results suggest that DNA-PKcs deficiency is not tolerated equally in all species, perhaps providing insight into why DNA-PKcs deficiency has not been observed in humans. Finally, this study demonstrates the feasibility of maintaining SCID dogs for extended periods of time and documents their utility for bone marrow transplantation studies and as hosts for the propagation of xenografts. In sum, SCID dogs may present researchers with new possibilities for the development of animal models of human disease.
Meek
Katheryn
K
Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan StateUniversity, East Lansing, MI 48824, USA. kmeek@msu.edu
Jutkowitz
Ari
A
Allen
Lisa
L
Glover
Jillian
J
Convery
Erin
E
Massa
Alisha
A
Mullaney
Tom
T
Stanley
Bryden
B
Rosenstein
Diana
D
Bailey
Susan M
SM
Johnson
Cheri
C
Georges
George
G
D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D004285:Dogs; D004622:Embryo, Mammalian / Q000276:immunology / Q000473:pathology; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000276:immunology; D006130:Growth Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics / Q000276:immunology*; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000473:pathology