Bcl-x_Lis an Antiapoptotic Regulator for Postnatal CNS Neurons

Abstract

Bcl-xL is a death-inhibiting member of the Bcl-2/Ced9 family of proteins which either promote or inhibit apoptosis. Gene targeting has revealed that Bcl-xL is required for neuronal survival during brain development; however, Bcl-xL knock-out mice do not survive past embryonic day 13.5, precluding an analysis of Bcl-xL function at later stages of development. Bcl-xL expression is maintained at a high level postnatally in the CNS, suggesting that it may also regulate neuron survival in the postnatal period. To explore functions of Bcl-xL related to neuron survival in postnatal life, we generated transgenic mice overexpressing human Bcl-xL under the control of a pan-neuronal promoter. A line that showed strong overexpression in brainstem and a line that showed overexpression in hippocampus and cortex were chosen for analysis. We asked whether overexpression of Bcl-xL influences neuronal survival in the postnatal period by studying two injury paradigms that result in massive neuronal apoptosis. In the standard neonatal facial axotomy paradigm, Bcl-xL overexpression had substantial effects, with survival of 65% of the motor neurons 7 d after axotomy, as opposed to only 15% in nontransgenic littermates. To investigate whether Bcl-xL regulates survival of CNS neurons in the forebrain, we used a hypoxia-ischemia paradigm in neonatal mice. We show here that hypoxia-ischemia leads to substantial apoptosis in the hippocampus and cortex of wild-type neonatal mice. Furthermore, we show that overexpression of Bcl-xL is neuroprotective in this paradigm. We conclude that levels of Bcl-xL in postnatal neurons may be a critical determinant of their susceptibility to apoptosis.

Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

“…18 We thus compared Bcl-xL with Drp1 K38A , and asked whether Bcl-xL might, directly or indirectly, have similar effects on mitochondrial morphology as well. dCSM cells were treated with recombinant Bcl-xL fused to a Tat protein transduction domain (Tat-Bcl-xL), which is delivered intracellularly and acts anti-apoptotically as shown before.…”

Bcl-XL modulates the differentiation of immortalized human neural stem cells

“…9,13,14 Bcl-X L is required for neuronal survival during brain development and in the postnatal period. 16 Indeed, extensive apoptotic cell death was observed in the developing brain of Bcl-X Ldeficient mice embryos. 15 Bcl-X L has also been recently reported to play a crucial role in neuronal development/ survival in conditional null mice specific for catecholaminergic cells.…”

“…[11][12][13][14] More specifically, Bcl-X L is essential for neuronal survival during brain development and in the adult central nervous system (CNS) (knockout mice and gene-expression studies 15,16 ). In addition to its antiapoptotic role, recent studies have described new roles of Bcl-X L in cell physiology -effects on Ca 2 þ homeostasis and gene expression 17 and synaptic transmission regulation 18 -under not necessarily apoptotic conditions.…”

Anti-apoptotic therapy with a Tat fusion protein protects against excitotoxic insults in vitro and in vivo

“…The protein is a member of the Bcl-2 family, is expressed in adult neurons of the CNS, and can play an essential role in preventing neuron cell death (Gonzalez-Garcia et al, 1995;Motoyama et al, 1995;Kharbanda et al, 1997;Parsadanian et al, 1998;Sastry and Rao, 2000). Bcl-xL, specifically the conserved N-terminal homology domain (BH4), is localized primarily in the mitochondrial membrane and the nuclear envelope , and prevents cytochrome c release and the decline of mitochondrial potential by directly modulating the activity of the voltage-dependent anion channels (Kluck et al, 1997;Yang et al, 1997;Susin et al, 1999;Shimizu et al, 2000); in addition, there are reports of Bcl-xL interacting with caspases (Hu et al, 1998;Pan et al, 1998).…”

“…The present study utilizes a CPP-protein therapy approach, using a fusion protein combining the Tat-PTD protein with a fragment of Bcl-xL, a well-characterized member of the antiapoptotic Bcl-2 family (Gonzalez-Garcia et al, 1995;Motoyama et al, 1995;Parsadanian et al, 1998). Specifically, we have used the conserved N-terminal homology domain (BH4) of Bcl-xL, which appears essential to the neuroprotective effects of the entire protein .…”