Multiple transcription factor families regulate axon growth and regeneration

Abstract

Understanding axon regenerative failure remains a major goal in neuroscience, and reversing this failure remains a major goal for clinical neurology. While an inhibitory CNS environment clearly plays a role, focus on molecular pathways within neurons has begun to yield fruitful insights. Initial steps forward investigated the receptors and signaling pathways immediately downstream of environmental cues, but recent work has also shed light on transcriptional control mechanisms that regulate intrinsic axon growth ability, presumably through whole cassettes of gene target regulation. Here we will discuss transcription factors that regulate neurite growth in vitro and in vivo, including p53, SnoN, E47, CREB, STAT3, NFAT, c-Jun, ATF3, Sox11, NFκB, and Kruppel-like factors (KLFs). Revealing the similarities and differences among the functions of these transcription factors may further our understanding of the mechanisms of transcriptional regulation in axon growth and regeneration.

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

“…Furthermore, immunoblot analysis of the protein expression levels of the abundant chondroitinase sulfate proteoglycan (CSPG) aggrecan was not significantly different between the two genotypes at 3 and 28 d after SCI (data not shown). These data suggest an involvement of p53 in regulation of the expression of fibrotic scar-associated extracellular matrix components but not of proteoglycans (Moore and Goldberg, 2011).…”

“…Values are expressed as averages Ϯ SEM. Student's t test, *p Յ 0.05. sprouting and regeneration (Silver and Miller, 2004;Yiu and He, 2006) and to the limited intrinsic neuronal capacity to regrow damaged axons (Di Giovanni, 2009;Moore and Goldberg, 2011). Our findings suggest that the transcription factor p53 modulates both the extrinsic spinal inhibitory environment and the intrinsic capacity of CNS neurons affecting the recovery of motor function in response to a traumatic event.…”

“…In p53 Ϫ/Ϫ injured cords, aberrant glial proliferation is accompanied by enhanced glial scar formation, as shown by GFAP-and fibronectin-positive scar tissue revealing a bigger reactive astrocyte area around the lesion site and an enlarged lesion core. Furthermore, mRNA expression analysis of the lesion site shows that genes associated with the fibrotic scar, including fibronectin, collagen 1␣2, and collagen 4␣1 (Stichel et al, 1999;Klapka et al, 2005;Moore and Goldberg, 2011) are differentially expressed in the absence of p53 following SCI. This observation gives us an insight of additional possible molecular components and mechanisms that contribute to the limited locomotor functional recovery we observed in p53 Ϫ/Ϫ mice after SCI.…”

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

“…During DNA replication, Dnmt1 regulates transfer of the DNA methylation pattern from the parent DNA strand to the new daughter strand. Other Dnmts, Dnmt3a and Dnmt3b are known as de novo Dnmts as they set in place new patterns of methylation of unmodified DNA [67]. In mature post-mitotic cells, such as CNS neurons, Dnmt expression is downregulated but still expressed, which suggests a role in CNS neuronal functions [68,69].…”

“…In mature post-mitotic cells, such as CNS neurons, Dnmt expression is downregulated but still expressed, which suggests a role in CNS neuronal functions [68,69]. In fact, some of the highest DNA methylation levels occur in brain tissue [67].…”