Bcl-2 promotes regeneration of severed axons in mammalian CNS

Chen, Dong Feng; Schneider, Gerald; Martinou, Jean‐Claude; Tonegawa, Susumu

doi:10.1038/385434a0

Cited by 420 publications

(295 citation statements)

References 29 publications

Supporting

Mentioning

276

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, a simple down-regulation of a single receptor cannot account for the change because postnatal RGCs fail to rapidly extend axons in response to all tested axon growth-promoting stimuli and substrates. The anti-apoptotic protein Bcl-2 was proposed as an intrinsic genetic switch that decreases axon growth rate by RGCs (Chen et al 1997), but Bcl-2 overexpression by purified RGCs in culture neither promotes axon growth nor enhances axon growth in response to neurotrophic signaling in vitro or in vivo (Goldberg et al 2002b), a result consistent with other findings (Greenlund et al 1995;Michaelidis et al 1996;Chierzi et al 1999;Goldberg and Barres 2000;Lodovichi et al 2001).…”

Section: What Molecular Changes Underlie the Developmental Loss In Rasupporting

confidence: 80%

How does an axon grow?

Goldberg¹

2003

Genes Dev.

203

138

View full text Add to dashboard Cite

How do axons grow during development, and why do they fail to regrow when injured? In the complicated mesh of our nervous system, the axon is the information superhighway, carrying all of the data we use to sense our environment and carry out behaviors. To wire up our nervous system properly, neurons must elongate their axons during development to reach their targets. This is no simple task, however. The complex morphology of axons and dendrites puts neurons among the most intricate and beautiful cells in the body. Knowledge of how neurons extend axons and dendrites, elongate at a particular rate, and stop growing at the proper time is critical to understanding the development of our nervous system, yet the regulation of these processes is poorly understood. Considerable attention in recent years has focused on understanding how growth cones are guided and steered through complicated pathways (for review, see Schmidt and Hall 1998;Mueller 1999), and even how neurons initiate new processes (for review, see Da Silva and Dotti 2002), but what mechanisms are involved in elongation itself? Are environmental signals needed to drive axon growth and, if so, what are the intracellular molecular mechanisms by which they induce elongation? What controls the rate of axon growth? How do CNS neurons know whether to extend axons or dendrites? Is the signaling of axon versus dendrite growth attributable to different extracellular signals, different neuronal states, or both? All of these questions bear critically on our understanding of axon growth and here I review recent answers and approaches to the above questions, and highlight their relevance during development, injury, and disease.

show abstract

Section: What Molecular Changes Underlie the Developmental Loss In Rasupporting

confidence: 80%

How does an axon grow?

Goldberg¹

2003

Genes Dev.

203

138

View full text Add to dashboard Cite

show abstract

“…This view is also supported by the trophic effect exerted by the grafts, which is reminiscent of the rescue of axotomized neurons by similar transplants observed in other systems (Villegas-Perez et al, 1988;Barron et al, 1989;Tetzlaff et al, 1994). Our results, however, indicate that retrograde trophic effects and growth-promoting actions may be dissociated phenomena (also see Chen et al, 1997).…”

Section: Transgenic Purkinje Cells Degenerate After Axotomy But Theysupporting

confidence: 30%

Targeted Overexpression of the Neurite Growth-Associated Protein B-50/GAP-43 in Cerebellar Purkinje Cells Induces Sprouting after Axotomy But Not Axon Regeneration into Growth-Permissive Transplants

et al. 1997

View full text Add to dashboard Cite

B-50/GAP-43 is a nervous tissue-specific protein, the expression of which is associated with axon growth and regeneration. Its overexpression in transgenic mice produces spontaneous axonal sprouting and enhances induced remodeling in several neuron populations (Aigner et al., 1995;Holtmaat et al., 1995). We examined the capacity of this protein to increase the regenerative potential of injured adult central axons, by inducing targeted B-50/GAP-43 overexpression in Purkinje cells, which normally show poor regenerative capabilities. Thus, transgenic mice were produced in which B-50/GAP-43 overexpression was driven by the Purkinje cell-specific L7 promoter. Uninjured transgenic Purkinje cells displayed normal morphology, indicating that transgene expression does not modify the normal phenotype of these neurons. By contrast, after axotomy numerous transgenic Purkinje cells exhibited profuse sprouting along the axon and at its severed end. Nevertheless, despite these growth phenomena, which never occurred in wild-type mice, the severed transgenic axons were not able to regenerate, either spontaneously or into embryonic neural or Schwann cell grafts placed into the lesion site. Finally, although only a moderate Purkinje cell loss occurred in wild-type cerebella after axotomy, a considerable number of injured transgenic neurons degenerated, but they could be partially rescued by the different transplants placed into the lesion site. Thus, B-50/GAP-43 overexpression substantially modifies Purkinje cell response to axotomy, by inducing growth processes and decreasing their resistance to injury. However, the presence of this protein is not sufficient to enable these neurons to accomplish a full program of axon regeneration.

show abstract

“…Bcl-2 appears to inhibit apoptotic cell death by regulating an antioxidant pathway that limits free radical generation. 11,16,25 The subsequent decrease in reactive oxygen species which are known to be detrimental to cellular function, may play an important role in the secondary injury cascade of spinal cord injury. 26,27 Just prior to submission of this manuscript, a report con®rming apoptotic cell death following spinal cord injury in rats and monkeys was noted.…”

Section: Discussionmentioning

confidence: 99%