Bcl-2, a proto-oncogene discovered at the chromosomal breakpoint of human follicular B cell lymphoma, is a death repressor that functions in many cell types in the adult. I sought to determine if Bcl-2 would be important in the broader context of the regulation of cell death during development. Immunohistochemical analysis demonstrates that Bcl-2 is widely expressed through mid-gestation within the fetal mouse in tissues derived from all 3 germ layers, becoming cell-type restricted as organs mature. The limb bud provides one clear example where Bcl-2 is restricted to zones of cell survival;​ Bcl-2 is expressed in the emerging digital zones, but not in the interdigital zones of cell death. The thymus is another organ in which Bcl-2 expression is inversely correlated with cell death. Bcl-2 is expressed in immature CD4⁻8⁻ thymocytes and in all mature CD4⁺ and CD8⁺ thymocytes, but is not present in most CD4⁺8⁺ cells which are highly susceptible to apoptosis at this intermediate stage of development. However, Bcl-2 is also expressed in many fetal tissues such as intestine and lung for which extensive developmental cell death has not been described, suggesting that expression of this death repressor is a common feature of many immature populations. In addition, even in tissues such as the nervous system where cell death is prominent, Bcl-2 expression does not always correlate temporally and topographically with susceptibility to cell death. The wide distribution of Bcl-2 in the developing mouse suggests that Bcl-2 may have roles beyond regulating cell death.

In order to investigate the roles of Bcl-2 in vivo, Bcl-2 deficient mice were generated by gene targeting in embryonic stem cells. Bcl-2 deficient mice complete embryonic development, but display growth retardation and early mortality post-natally. Hematopoiesis including lymphocyte differentiation is initially normal, but thymus and spleen undergo massive apoptotic involution. Renal failure results from severe polycystic kidney disease. Bcl-2 deficient mice turn gray with the second hair follicle cycle, implicating a defect in redoxregulated melanin synthesis. The spectrum of abnormalities in these mice support the hypothesis that Bcl-2 acts in an anti-oxidant pathway which regulates cell survival and other metabolic functions.