Gsx1 promotes locomotor functional recovery after spinal cord injury

Abstract

Promoting residential cells, particularly endogenous neural stem and progenitor cells (NSPCs), for tissue regeneration represents a potential strategy for the treatment of spinal cord injury (SCI). However, adult NSPCs differentiate mainly into glial cells and contribute to glial scar formation at the site of injury. Gsx1 is known to regulate the generation of excitatory and inhibitory interneurons during embryonic development of the spinal cord. In this study, we show that lentivirus-mediated expression of Gsx1 increases the number of NSPCs in a mouse model of lateral hemisection SCI during the acute stage. Subsequently, Gsx1 expression increases the generation of glutamatergic and cholinergic interneurons and decreases the generation of GABAergic interneurons in the chronic stage of SCI. Importantly, Gsx1 reduces reactive astrogliosis and glial scar formation, promotes serotonin (5-HT) neuronal activity, and improves the locomotor function of the injured mice. Moreover, RNA sequencing (RNA-seq) analysis reveals that Gsx1induced transcriptome regulation correlates with NSPC signaling, NSPC activation, neuronal differentiation, and inhibition of astrogliosis and scar formation. Collectively, our study provides molecular insights for Gsx1-mediated functional recovery and identifies the potential of Gsx1 gene therapy for injuries in the spinal cord and possibly other parts of the central nervous system.

Gsx2 but not Gsx1 is necessary for early forebrain patterning and long-term survival in zebrafish

“…Gsx2 mutant mice fail to survive more than a day following birth, however also exhibit severely disrupted forebrain and hindbrain morphology. Comprehensive knowledge of GSX1 and GSX2 function together and separately is minimal outside of the mouse forebrain 34,44,51 and few reports in the cerebellum 30,46,77 and spinal cord 7,10,48 . As such, analysis of Gsx1 and Gsx2 function in our zebrafish mutants in these and other CNS regions can supplement these reports.…”

“…Through a Notch signaling dependent mechanism, Gsx1 and Gsx2 regulate the temporal specification of glutamatergic and GABAergic interneurons in the mouse spinal cord 7 . In this region Gsx1 also promotes neural stem and progenitor cell generation and decreases reactive glial scar formation to facilitate recovery from injury 48 . gsx1 is implicated as a molecular marker of glutamatergic interneurons in the dorsal brainstem in zebrafish that regulate the acoustic startle response, and zebrafish with ablated gsx1-expressing neurons and mouse Gsx1 knockouts similarly exhibit disrupted responsiveness to single and paired pulse acoustic-vibrational stimuli 28,49 .…”

Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease

“…Gsx1 further promoted neuronal differentiation over glial lineage in the injured spinal cord (Figure 3C). This resulted in an increased number of neurons, reduced reactive astrocytes and glial scar formation, and improved functional recovery [66].…”

“…The canonical Notch signaling pathway is required to regulate the quiescence, proliferation, and differentiation of NSPCs in the CNS [43,[65][66][67]. The Cai lab identified a 399bp cis-element in the second intron of the Notch1 locus (CR2) [68].…”

“…The activities of Notch pathway and NSPCs can be traced by the reporter GFP expression (Figure 3A). The cell fate of GFP tagged interneuron progenitors have been characterized in both normal development and neurological disease/injury conditions, which facilitate the study of the potentials of NSPCs in regenerative medicine [43,66,68]. In these studies, the Cai lab has demonstrated that GFP+ NSPCs preferentially differentiate into interneurons of the brain and spinal cord during embryonic development and in adulthood [43,67].…”