A Transcription-Dependent Switch Controls Competence of Adult Neurons for Distinct Modes of Axon Growth

Abstract

Although maturing neurons undergo a precipitous decline in the expression of genes associated with developmental axon growth, structural changes in axon arbors occur in the adult nervous system under both normal and pathological conditions. Furthermore, some neurons support extensive regrowth of long axons after nerve injury. Analysis of adult dorsal root ganglion (DRG) neurons in culture now shows that competence for distinct types of axon growth depends on different patterns of gene expression. In the absence of ongoing transcription, newly isolated neurons can extend compact, highly branched arbors during the first day in culture. Neurons subjected to peripheral axon injury 2-7 d before plating support a distinct mode of growth characterized by rapid extension of long, sparsely branched axons. A transition from "arborizing" to "elongating" growth occurs in naive adult neurons after ϳ24 hr in culture but requires a discrete period of new transcription after removal of the ganglia from the intact animal. Thus, peripheral axotomy-by nerve crush or during removal of DRGsinduces a transcription-dependent change that alters the type of axon growth that can be executed by these adult neurons. This transition appears to be triggered, in large part, by interruption of retrogradely transported signals, because blocking axonal transport in vivo can elicit competence for elongating growth in many DRG neurons. In contrast to peripheral axotomy, interruption of the centrally projecting axons of DRG neurons in vivo leads to subsequent growth in vitro that is intermediate between "arborizing" and "elongating" growth. This suggests that the transition between these two modes of growth is a multistep process and that individual steps may be regulated separately. These observations together suggest that structural remodeling in the adult nervous system need not involve the same molecular apparatus as long axon growth during development and regeneration.

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat

“…The success of the regenerative attempts by the injured CNS also appears dependent on the capacity of injured neurons to express intrinsic molecular machinery required for neurite elongation, generally thought to be inhibited in mature intact CNS neurons (Smith and Skene, 1997;Bouslama-Oueghlani et al, 2003). Adult neuronal populations upregulate regenerationassociated genes (RAGs) after axotomy (Tetzlaff et al, 1991;Schaden et al, 1994;Bonilla et al, 2002;Tanabe et al, 2003;Fischer et al, 2004), and axonal sprouting following CNS injury, including TBI, may be accompanied by reinduction of genes ordinarily associated with developmental axonal growth (Emery et al, 2000;Abankwa et al, 2002;Emery et al, 2003;Mason et al, 2003).…”

How does an axon grow?

“…Even more interestingly, axon growth requires the transcription of genes specific for axon elongation. This was demonstrated beautifully in experiments showing that after injuring the peripheral axon of DRG neurons in vivo, they switch from a branching mode of axon growth to an elongation mode, and this switch requires new gene transcription (Smith and Skene 1997). Other genes have been found to be upregulated during regeneration (Bonilla et al 2002), and it is not known whether these and other candidate genes coming from global gene expression studies in progress will have a role in the various processes discussed above, or will open up entirely new areas in the study of axon growth.…”

“…After a day in culture, they revert into a rapidly elongating, minimally branching mode, and a transcription-dependent switch discussed above controls the competence of these neurons to elongate their axons. This transition can be elicited in vivo by injuring the PNS axon a few days before explanting the neuron, a paradigm called a "conditioning lesion," but this change to an elongation mode either in vivo or in vitro typically involves an increase in growth rate of about twofold (Smith and Skene 1997). Therefore, both CNS and PNS neurons show an intrinsic state dependence in their axon growth ability, but whereas PNS neurons remain fairly true to their developmental axon growth ability and quickly revert to this fast elongation when called on to regenerate their axons, RGCs and possibly other CNS neurons dramatically lose their developmental axon growth ability and fail to revert to a rapidly regenerating mode after injury.…”

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

“…The axon growth-associated gene program is thought to be inhibited in mature intact neurons, most likely through retrograde extrinsic influences (Skene, 1989(Skene, , 1992Smith and Skene, 1997). Nevertheless, several adult neuron populations upregulate growthassociated genes after axotomy, and this expression is related to their ability to regenerate their axons into growth-permissive territories (C ampbell et al, 1991;Tetzlaff et al, 1991Tetzlaff et al, , 1994Schaden et al, 1994).…”