baxDeficiency Prevents the Increased Cell Death of Immature Neurons inbcl-x-Deficient Mice

Abstract

The intracellular balance between pro-and antiapoptotic members of the Bcl-2 gene family is thought to regulate cell death. Targeted disruption of bcl-x, a death repressing member, causes massive cell death of immature neurons in the developing mouse CNS, whereas targeted disruption of bax, a proapoptotic member, blocks the death of specific populations of sympathetic and motor neurons. In the present study, mice deficient in both Bcl-x L and Bax (bcl-x Ϫ/Ϫ /bax Ϫ/Ϫ ) are used to examine the relative significance and potential interactions of Bcl-x L and Bax during early CNS development. bcl-x Ϫ/Ϫ / bax Ϫ/Ϫ mice demonstrate greatly reduced levels of apoptosis both in vivo and in vitro compared with the CNS of Bcl-x Ldeficient mice, as assessed by histology and terminal deoxytransferase-mediated deoxyuridine triphosphate nick end-labeling. Bax-deficient mice, however, contain occasional apoptotic cells in the developing CNS, and cultures of baxdeficient telencephalic cells demonstrate similar levels of apoptosis as wild-type cultures. These results suggest that Bax critically interacts with Bcl-x L to regulate survival of immature neurons, but indicate that other cell death regulating proteins, in addition to Bcl-x L and Bax, also function during CNS development.

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

“…Bax de®ciency causes accelerated proliferation of a transgenic brain tumor , indicating that Bax functions as a tumor suppressor gene. Bax 7/7 Bcl-X 7/7 do not manifest the increased cell death of immature neurons observed in Bax +/+ Bcl-X 7/7 mice (Shindler et al, 1997). Similarly, the thymic hypoplasia characteristic of Bcl-2 7/7 mice is largely absent in mice also de®cient in Bax , underlining the importance of an equilibrium between pro-apoptotic (Bax) and anti-apoptotic (Bcl-2, Bcl-X L ) proteins for the regulation of cell survival.…”

Distinct susceptibility of developing neurons to death following Bax overexpression in the chicken embryo

“…2 Other studies pointed out that the expression of Bax increases during PCD, as well as under pathological conditions. 3,6,[10][11][12][13] In the present studies, we initially examined the effects of Bax overexpression on several different neuronal populations that undergo normal PCD. These include the early phase of developing retinal PCD which appears to be induced by death signaling through NGF and TGF-b, 30,31 as well as the common type of neuronal PCD that occurs in developing sensory and MNs of the spinal cord after forming synaptic connections with targets.…”

“…Previous studies suggested that a balance between anti-versus proapoptotic Bcl-2 family members determine the susceptibility of cells to die. 3,6,10 Other cellular factors such as heat shock protein (HSP) 27 may be involved in regulating survival and death of neurons. 33 Thus, whether a neuron lives or dies during the period of developmental PCD may be regulated by both extrinsic (e.g., neurotrophic factors) and intrinsic (e.g.…”

“…1 Bax, a proapoptotic member of the Bcl-2 family, is widely expressed in the nervous system during development 2,3 and is required for neuronal death since Bax deficiency has been demonstrated to prevent developmental and induced neuronal death. 2,[4][5][6] Although the necessity of Bax for normal PCD of many neuronal populations during development is well recognized, several questions remain concerning the specific role of Bax in neuronal survival and death in vivo.…”

“…On the other hand, the intracellular balance between anti-versus proapoptotic Bcl-2 family members is important in determining whether cells survive or die. 3,6,10 The balance can be changed in favor of proapoptosis in several pathological conditions which cause neuronal damage. [11][12][13] It has been previously reported that overexpression of Bax induces death of cultured neurons in the absence of obvious apoptotic stimuli.…”