Defining the role of the Bcl-2 family of proteins in the nervous system.

The Bcl-2 family of apoptotic-regulating proteins plays important roles during both neural development and maintenance of tissue homeostasis. The major antiapoptotic family members, Bcl-x(L) and Bcl-2, and the major proapoptotic proteins, Bax and Bak, show distinct temporal and spatial patterns of expression in the developing brain. Targeted deletions of Bcl-x(L) and Bcl-2 as well as Bax and Bak have proven to be important tools in delineating the process of cell death in the nervous system. These genetic models show that Bcl-x(L) and Bax play crucial roles in regulating the survival of differentiating neurons. In contrast, Bax and Bak play redundant roles in regulating the size of the neural progenitor cell population in postnatal mice and in the normal development of the retinal layers of the eye. Bax, Bcl-x(L), and Bcl-2 regulate the apoptotic response to neurotrophic factor deprivation. In contrast, excitotoxic cell death is not dependent on either Bax or Bak. In fact, the absence of proapoptotic Bcl-2 proteins can enhance the toxicity of neuroexcitatory molecules. Together, these data establish the intrinsic apoptotic pathway regulated by Bcl-2 proteins as a critical but not exclusive regulator of neural cell survival.