The nuclear events guiding successful nerve regeneration

Abstract

Peripheral nervous system (PNS) neurons survive and regenerate after nerve injury, whereas central nervous system (CNS) neurons lack the capacity to do so. The inability of the CNS to regenerate presumably results from a lack of intrinsic growth activity and a permissive environment. To achieve CNS regeneration, we can learn from successful nerve regeneration in the PNS. Neurons in the PNS elicit dynamic changes in gene expression in response to permissive environmental cues following nerve injury. To switch gene expression on and off in injured neurons, transcription factors and their networks should be carefully orchestrated according to the regeneration program. This is the so-called "intrinsic power of axonal growth." There is an increasing repertoire of candidate transcription factors induced by nerve injury. Some of them potentiate the survival and axonal regeneration of damaged neurons in vivo; however, our knowledge of transcriptional events in injured neurons is still limited. How do these transcription factors communicate with each other? How does the transcriptional machinery regulate the wide variety of regeneration-associated genes (RAGs) in the properly coordinated manner? In this review, we describe our current understanding of the injury-inducible transcriptional factors that enhance the intrinsic growth capacity, and propose a potential role for specificity protein 1 (Sp1), which provides a platform to recruit injury-inducible transcription factors, in simultaneous gene regulation. Finally, we discuss an additional mechanism that is involved in epigenetic modifications in damaged neurons. A comprehensive understanding of the nuclear events in injured neurons will provide clues to clinical interventions for successful nerve regeneration.

Keywords: ATF3; DINE; STAT3; Sp1; axotomy; c-Jun; nerve injury; transcription.

Figure 1

Peripheral nerve injury elicits a dynamic change in the transcription of regeneration-associated genes (RAGs) to enhance intrinsic growth capacity in neurons. The transcription factors involved in nerve regeneration are expressed at low-level in normal neurons. RAGs are expressed at low-level or switched off. Upon axotomy, microglial cells and subsequent astrocytes surround the cell body of injured neuron. Synaptic terminals are detached from the cell body. At the injury site, Schwann cells undergo dedifferentiation and proliferation, and Schwann cells and macrophages rapidly remove myelin debris. The local permissive environment provides the injury signals via cell surface receptors of the cell body and via retrograde axonal transport from growth cone. The signals induce the expression of numerous transcription factors, modify them at the post-translational level and lead to form various types of transcriptional complex, to promote the RAGs expression (See main text for details).

Figure 2

Possible mechanism of the Sp1-mediated transcriptional machinery to induce the regeneration-associated gene DINE in response to nerve injury. (A) Transcriptional regulation of DINE before and after nerve injury. In the normal conditions, Sp1 and the unknown transcriptional complex express DINE at the low-level. Following nerve injury, injury-inducible transcription factor ATF3 form a heterodimer with cJun and Sp1 provides a platform to recruit ATF3, c-Jun, and Stat3. (B) The activity of Sp1 can be regulated by post-translational modifications including phosphorylation, acetylation, ubiquitination. Additional transcription factors and chromatin modifiers may participate in the Sp1-mediated transcriptional complex shown in (A).

Figure 3

The possible involvement of epigenetic modification during nerve regeneration. In addition to the involvement of numerous transcriptional factors shown in Figure 1, the epigenetic modification of chromatin structure might affect the gene expression following nerve injury. Both histone modification including acetylation and phosphorylation and DNA modification such as methylation are associated with active gene expression as well as gene repression. Furthermore, microRNAs are implicated as potent silencers of gene expression.