Identification of Intrinsic Axon Growth Modulators for Intact CNS Neurons after Injury

Abstract

SUMMARY Functional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma and are thought to be mediated by the plasticity of intact circuitry. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from Ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators LPPR1 and LPAR1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo LPAR1 inhibition or LPPR1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild-type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation.

Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration

“…This study avoided any issues related to tissue culture prior to expression analysis, but the overlap with functional axon regeneration genes remained minimal with 5 genes in total, and was non-significant (Figure S2A). The functional regeneration genes were identified here in cortical neurons, so we also assessed overlap with our RNA-seq expression profile of sprouting corticospinal neurons after pyramidotomy (Fink et al, 2017). This expression survey also revealed minimal and statistically insignificant overlap with functional effects on axon regeneration, though the absolute numbers were higher than for the DRG studies (Figure S2B).…”

“…In contrast, the most common approach to identifying genes involved in regeneration has focused on expression surveys, most commonly at the mRNA level (Belin et al, 2015; Bonilla et al, 2002; Chandran et al, 2016; Fink et al, 2017; Tanabe et al, 2003; Tedeschi et al, 2016). Such previous work has the premise that genes involved in regulating regeneration are controlled transcriptionally by injury.…”

Maximizing functional axon repair in the injured central nervous system: Lessons from neuronal development

“…Analyses revealed that components of the lysophosphatidic acid (LPA) pathway were differentially expressed, with a substantial suppression of LPA receptor 1 (Lpar1) in actively sprouting neurons. Administration of AM095, a small molecule inhibitor of Lpar1, improved CST sprouting and motor behaviors in mice that had undergone unilateral pyramidotomy (Fink et al, ). These exciting results pave the way for further exploration of new targets and pharmacological agents to enhance axonal sprouting and functional recovery.…”

Efficient differentiation and polarization of primary cultured neurons on poly(lactic acid) scaffolds with microgrooved structures

“…Neuroligins interact with neurexins, a family of presynaptic adhesion molecules, and are major regulators of synapse development and function 30 . Interestingly, Inpp5k has been reported to act as a lysophosphatidic acid signaling modulator, and its overexpression promotes the intrinsic axon growth of corticospinal axons 31 . Considering these reports and the results of our NGS analysis, it is presumed that neurons cultured on the microgrooved nanosheet become more mature than neurons cultured on the flat nanosheet.…”