DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7.In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced.In vivo, young adult C57BL/6 mice received a T10 contusion followed by an AAV-KLF7 injection at the T7–9 levels above the lesion. Five weeks later, overexpression of KLF7 was expressed in DPSN. KLF7 and KLF7 target genes (NGF, TrkA, GAP43, and P0) were detectably increased in the injured spinal cord. Myelin sparring at the lesion site, DPSN axonal regeneration and synapse formation, muscle weight, motor endplate morphology, and functional parameters were all additionally improved by KLF7 treatment. Our findings suggest that KLF7 promotes DPSN axonal plasticity and the formation of synapses with motor neurons at the caudal spinal cord, leading to improved functional recovery and further supporting the potential of AAV-KLF7 as a therapeutic agent for spinal cord injury.

. The role of Chx10+V2a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2a interneurons also play an important role in rhythmic patterning maintenance, left-right alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2a interneurons transplanted in spinal cord injury foci....

Objective: Krüppel-like Factor 7 (KLF7) is a transcription factor that promotes axon regeneration in the central nervous system. Here, we assessed whether KLF7 stimulates regeneration after peripheral nerve injury. Methods: C57BL/6 mice received an acellular nerve allograft (ANA) injected with either adeno-associated virus 2 (AAV2) vector or AAV2-KLF7 for sciatic nerve gap repair. After 4 weeks, KLF7 was detected by RT-PCR, western blot and immunohistochemistry in regenerated nerves. Axonal regeneration and functional recovery were examined by immunohistochemistry, Fluorogold (FG) and cholera toxin B (CTB) retrograde neural tracing, sciatic function index (SFI), angle of ankle, Hargreaves test and electrophysiological analysis. Results: With AAV2-KLF7 injection, KLF7 expression increased in regenerated nerves, and amplitude, score of SFI, angle of ankle and FG-labelled spinal cord neurons were increased. We observed elevated CTB-labelled neurons in dorsal root ganglia (DRG), neurofilaments, P₀ (peripheral myelin) and S100 and decreased latency period and withdrawal latencies in the Hargreaves test. The SFI was significantly correlated with amplitude and regenerated axon number. Tyrosine kinase A (TrkA) and B (TrkB) receptors were also increased in the DRG. Conclusions: Our findings suggest that KLF7 promoted peripheral nerve axonal regeneration, further supporting a role for KLF7 as a growth-promoting transcription factor in the injured nervous system.

Spinal cord injury (SCI) causes irreversible motor deficits due to disrupted lumbar circuitry. However, transcriptional mechanisms in distal lumbar circuits are poorly understood. We identify POU6F1 as a critical transcriptional regulator in spinal lumbar segment (SLS, L3-L5) motor circuit regeneration. Using an integrative approach combining a T9 contusion SCI model, primary motor neurons (MNs) cultures exposed to OGD/R, RNA sequencing, anterograde/retrograde neural tracing, IncuCyte® ZOOM live-cell imaging, Co-IP, molecular docking, luciferase reporter assays, transmission electron microscopy, and other techniques, we identified sustained POU6F1 upregulation temporally coupled to endogenous SLS MNs axon regeneration after SCI. AAV-mediated POU6F1 overexpression activated JNK/c-Jun/GAP-43/BDNF signaling, rescuing MNs viability and promoting neurite outgrowth, however, these restorative effects were fully abolished by JNK inhibition. POU6F1 overexpression in SLS MNs enhanced dendritic complexity, synaptic reorganization, and the descending propriospinal tract (dPST) axonal growth. This overexpression further attenuated SCI-induced dendritic pathology, drove remodeling of the SLS motor circuit, and culminated in tibialis anterior (TA) muscle reinnervation and locomotor recovery. Mechanistically, POU6F1 directly bound JNK and transactivated the c-Jun promoter, thereby driving downstream effectors GAP-43 and BDNF/TrkB expression to synergistically enhancing intrinsic neurite outgrowth and microenvironmental remodeling. Our findings establish POU6F1 as the first transcription factor coordinating SLS motor circuit reorganization.