Protection of Retinal Ganglion Cells from Natural and Axotomy-Induced Cell Death in Neonatal Transgenic Mice Overexpressing bcl-2

Abstract

Approximately half of the retinal ganglion cells (RGCs) present in the rodent retina at birth normally die during early development. Overexpression of the proto-oncogene bcl-2 recently has been shown to rescue some neuronal populations from natural cell death and from degeneration induced by axotomy of nerves within the peripheral nervous system. Here we study in vivo the role of the overexpression of bcl-2 in the natural cell death of RGCs and in the degenerative process induced in these cells by transection of the optic nerve. We find that in newborn bcl-2 transgenic mice, the number of RGCs undergoing natural cell death is considerably lower than in wild-type pups. Consistently, a vast majority (90%) of the ganglion cells found in the retina of neonatal transgenics are maintained in adulthood, whereas only 40% survive in wild-type mice.After transection of the optic nerve, the number of degenerating ganglion cells, determined by counting pyknotic nuclei or nuclei with fragmented DNA, is substantially reduced in transgenic mice. In wild-type animals, almost 50% of ganglion cells degenerate in the 24 hr after the lesion, whereas almost the entire ganglion cell population survives axotomy in transgenic mice. Therefore, overexpression of bcl-2 is effective in preventing degeneration of this neuronal population, raising the possibility that ganglion cells are dependent on the endogenous expression of bcl-2 for survival. The remarkable rescue capacity of bcl-2 overexpression in these neurons makes it an interesting model for studying natural cell death and responses to injury in the CNS.

BaxInactivation in Lurcher Mutants Rescues Cerebellar Granule Cells But Not Purkinje Cells or Inferior Olivary Neurons

“…We have shown previously that overexpression of bcl-2 in Grid2 Lc/ϩ olivary neurons will rescue most of the olivary neurons from target-related cell death (Zanjani et al, 1998b). This result is consistent with previous studies showing in vitro rescue of neurons from trophic factor withdrawal (Garcia et al, 1992;Allsopp et al, 1993;Batistatou et al, 1993) and in vivo rescue of neurons from axotomy or ischemia by bcl-2 overexpression Martinou et al, 1994;Farlie et al, 1995;Bonfanti et al, 1996;De Bilbao and Dubois-Dauphin, 1996) or deletion of Bax expression (Deckwerth et al, 1996;White et al, 1998).…”

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

“…For example, overexpression of a bcl-2 transgene increases RGC survival after axotomy in neonatal mice (27) and maintains the longterm survival (29) and normal electrophysiological response (57) of axotomized RGCs in adult mice. Bcl-2 overexpression also promotes the RGC axons to regrow (58).…”

“…In Bcl-2 transgenic mice, Bcl-2 overexpression blocks naturally occurring neuronal death (26,27) and reduces axotomyinduced (27)(28)(29)(30), ischemia-induced (26), and chemically induced (31) neuronal death. Similarly, Bcl-XL overexpression inhibits axotomy-induced (32) and ischemia-induced apoptosis (32,33) in transgenic mice.…”

Deficiency of Bax and Bak protects photoreceptors from light damage in vivo

“…Overexpression of the antiapoptotic gene bcl-2, shown to reduce developmental apoptosis of neurons including ganglion cells, 20 protects ganglion cells from apoptosis following pathologic in vivo axotomy. 21 We have recently shown that deficiency of Bax and Bak blocks normal developmental apoptosis of rod photoreceptors, 3 and overexpression of bcl-x L , an antiapoptotic bcl-2 family member, blocks developmental lead exposure induced photoreceptor cell death. 22 Bcl-2 family members may similarly be involved in additional photoreceptor degenerations.…”