TARGETED DISRUPTION OF BCL-2-ALPHA-BETA IN MICE - OCCURRENCE OF GRAY HAIR, POLYCYSTIC KIDNEY-DISEASE, AND LYMPHOCYTOPENIA

Mice carrying ablated coding regions of the bcl-2 alpha and bcl-2 beta transcripts have been made. bcl-2(-)/(-) mutants are smaller but viab le, although about half of them die by 6 weeks of age. As shown earlie r with somatic bcl-2 gene-targeted mice, the number of lymphocytes mar kedly decreased within few weeks after birth while other hematopoietic lineages remained unaffected. Among lymphocytes, CD8(+) T cells disap peared most quickly followed by CD4(+) T cells, whereas B cells were l east affected. bcl-2(-)/(-) lymphocytes, however, could respond normal ly to various stimuli including anti-CD3, Con A, phorbol 12-myristate 13-acetate plus ionomycin, interleukin 2, lipopolysaccharide, and anti -IgM antibody. Abnormalities among nonlymphoid organs include smaller auricles, hair color turning gray at 4-5 weeks of age, and polycystic kidney disease-like change of renal tubules. These results suggest tha t Bcl-2 may be involved during morphogenesis where inductive interacti ons between epithelium and mesenchyme are important such as in the kid neys, hair follicles, and perichondrium of auricles. Surprisingly, the nervous system, intestines, and skin appear normal despite the fact t hat these organs show high levels of endogeneous Bcl-2 expression in n ormal mice.