Foxm1 regulates neural progenitor fate during spinal cord regeneration.
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ABSTRACT:
SUBMITTER: Pelzer D
PROVIDER: S-EPMC8419688 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesWe have evaluated the physiological roles of transforming growth factor-beta1 (TGF-beta1) on differentiation, migration, proliferation and anti-apoptosis characteristics of cultured spinal cord-derived neural progenitor cells.MethodsWe have used neural progenitor cells that had been isolated and cultured from mouse spinal cord tissue, and we also assessed the relevant reaction mechanisms using an activin-like kinase (ALK)-specific inhibitory system including an inhibitory RNA, and found that it involved potential signalling molecules such as phosphatidylinositol-3-OH kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK1/2).Results and conclusionsTransforming growth factor-beta1-mediated cell population growth was activated after treatment and was also effectively blocked by an ALK41517-synthetic inhibitor (4-(5-benzo(1,3) dioxol-5-yl-4-pyridine-2-yl-1H-imidazole-2-yl) benzamide (SB431542) and ALK siRNA, thereby indicating the involvement of SMAD2 in the TGF-beta1-mediated growth and migration of these neural progenitors cells (NPC). In the present study, TGF-beta1 actively induced NPC migration in vitro. Furthermore, TGF-beta1 demonstrated extreme anti-apoptotic behaviour against hydrogen peroxide-mediated apoptotic cell death. At low dosages, TGF-beta1 enhanced (by approximately 76%) cell survival against hydrogen peroxide treatment via inactivation of caspase-3 and -9. TGF-beta1-treated NPCs down-regulated Bax expression and cytochrome c release; in addition, the cells showed up-regulated Bcl-2 and thioredoxin reductase 1. They also had increased p38, Akt and ERK1/2 phosphorylation, showing the involvement of both the PI3K/Akt and MAPK/ERK1/2 pathways in the neuroprotective effects of TGF-beta1. Interestingly, these effects operate on specific subtypes of cells, including neurones, neural progenitor cells and astrocytes in cultured spinal cord tissue-derived cells. Lesion sites of spinal cord-overexpressing TGF-beta1-mediated prevention of cell death, cell growth and migration enhancement activity have been introduced as a possible new basis for therapeutic strategy in treatment of neurodegenerative disorders, including spinal cord injuries.
| S-EPMC6496837 | biostudies-literature
Project description:Early embryonic development of the spinal cord requires tight coordination between proliferation of neural progenitors and their differentiation into distinct neuronal cell types to establish intricate neuronal circuits. The Hippo pathway is one of the well-known regulators to control cell proliferation and govern neural progenitor cell number, in which the downstream effector Yes-associated protein (Yap) promotes cell cycle progression. Here we show that an atypical cadherin Fat3, expressed highly in the neural tube, plays a critical role in maintaining proper number of proliferating progenitors. Knockdown of Fat3 in chick neural tube down-regulates expression of the proliferation markers but rather induces the expression of neural markers in the ventricular zone. We further show that deletion of Fat3 gene in mouse neural tube depletes neural progenitors, accompanied by neuronal gene expression in the ventral ventricular zone of the spinal cord. Finally, we found that Fat3 regulates the phosphorylation level of Lats1/2, the upstream kinase of Yap, resulting in dephosphorylation and stabilization of Yap, suggesting Yap as a key downstream effector of Fat3. Our study uncovers another layer of regulatory mechanisms in controlling the activity of Hippo signaling pathway to regulate the size of neural progenitor pools in the developing spinal cord.
| S-EPMC9427758 | biostudies-literature
Project description:The adult mammalian spinal cord contains neural stem and/or progenitor cells that slowly multiply throughout life and differentiate exclusively into glia. The contribution of adult progenitors to repair has been highlighted in recent studies, demonstrating extensive cell proliferation and gliogenesis following central nervous system (CNS) trauma. The present experiments aimed to determine the relative roles of endogenously dividing progenitor cells versus quiescent progenitor cells in posttraumatic gliogenesis. Using the mitotic indicator bromodeoxyuridine (BrdU) and a retroviral vector, we found that, in the adult female Fisher 344 rat, endogenously dividing neural progenitors are acutely vulnerable in response to T8 dorsal hemisection spinal cord injury. We then studied the population of cells that divide postinjury in the injury epicenter by delivering BrdU or retrovirus at 24 hours after spinal cord injury. Animals were euthanized at five timepoints postinjury, ranging from 6 hours to 9 weeks after BrdU delivery. At all timepoints, we observed extensive proliferation of ependymal and periependymal cells that immunohistochemically resembled stem/progenitor cells. BrdU+ incorporation was noted to be prominent in NG2-immunoreactive progenitors that matured into oligodendrocytes, and in a transient population of microglia. Using a green fluorescence protein (GFP) hematopoietic chimeric mouse, we determined that 90% of the dividing cells in this early proliferation event originate from the spinal cord, whereas only 10% originate from the bone marrow. Our results suggest that dividing, NG2-expressing progenitor cells are vulnerable to injury, but a separate, immature population of neural stem and/or progenitor cells is activated by injury and rapidly divides to replace this vulnerable population.
| S-EPMC2553041 | biostudies-literature
Project description:Impact statementSpinal cord injury (SCI) results in loss of tissue innervation below the injury. Spinal progenitors have a greater ability to repair the damage and can be injected into the injury, but their regenerative potential is hampered by their poor survival after transplantation. Biomaterials can create a cell delivery platform and generate a more hospitable microenvironment for the progenitors within the injury. In this work, polymeric bridges are used to deliver embryonic spinal progenitors to the injury, resulting in increased progenitor survival and subsequent regeneration and functional recovery, thus demonstrating the importance of combined therapeutic approaches for SCI.
| S-EPMC6238608 | biostudies-literature
Project description:Neurogenesis requires the coordination of neural progenitor proliferation and differentiation with cell-cycle regulation. However, the mechanisms coordinating these distinct cellular activities are poorly understood. Here we demonstrate for the first time that a Cut-like homeodomain transcription factor family member, Cux2 (Cutl2), regulates cell-cycle progression and development of neural progenitors. Cux2 loss-of-function mouse mutants exhibit smaller spinal cords with deficits in neural progenitor development as well as in neuroblast and interneuron differentiation. These defects correlate with reduced cell-cycle progression of neural progenitors coupled with diminished Neurod and p27(Kip1) activity. Conversely, in Cux2 gain-of-function transgenic mice, the spinal cord is enlarged in association with enhanced neuroblast formation and neuronal differentiation, particularly with respect to interneurons. Furthermore, Cux2 overexpression induces high levels of Neurod and p27(Kip1). Mechanistically, we discovered through chromatin immunoprecipitation assays that Cux2 binds both the Neurod and p27(Kip1) promoters in vivo, indicating that these interactions are direct. Our results therefore show that Cux2 functions at multiple levels during spinal cord neurogenesis. Cux2 initially influences cell-cycle progression in neural progenitors but subsequently makes additional inputs through Neurod and p27(Kip1) to regulate neuroblast formation, cell-cycle exit and cell-fate determination. Thus our work defines novel roles for Cux2 as a transcription factor that integrates cell-cycle progression with neural progenitor development during spinal cord neurogenesis.
| S-EPMC3093760 | biostudies-literature
Project description: Not available
| S-EPMC9120701 | biostudies-literature
Project description:Axolotls are uniquely able to mobilize neural stem cells to regenerate all missing regions of the spinal cord. How a neural stem cell under homeostasis converts after injury to a highly regenerative cell remains unknown. Here, we show that during regeneration, axolotl neural stem cells repress neurogenic genes and reactivate a transcriptional program similar to embryonic neuroepithelial cells. This dedifferentiation includes the acquisition of rapid cell cycles, the switch from neurogenic to proliferative divisions, and the re-expression of planar cell polarity (PCP) pathway components. We show that PCP induction is essential to reorient mitotic spindles along the anterior-posterior axis of elongation, and orthogonal to the cell apical-basal axis. Disruption of this property results in premature neurogenesis and halts regeneration. Our findings reveal a key role for PCP in coordinating the morphogenesis of spinal cord outgrowth with the switch from a homeostatic to a regenerative stem cell that restores missing tissue.
| S-EPMC4755742 | biostudies-literature
Project description:Elevated expression of FoxM1 in breast cancer correlates with an undifferentiated tumor phenotype and a negative clinical outcome. However, a role for FoxM1 in regulating mammary differentiation was not known. Here, we identify another function of FoxM1, the ability to act as a transcriptional repressor, which plays an important role in regulating the differentiation of luminal epithelial progenitors. Regeneration of mammary glands with elevated levels of FoxM1 leads to aberrant ductal morphology and expansion of the luminal progenitor pool. Conversely, knockdown of FoxM1 results in a shift toward the differentiated state. FoxM1 mediates these effects by repressing the key regulator of luminal differentiation, GATA-3. Through association with DNMT3b, FoxM1 promotes methylation of the GATA-3 promoter in an Rb-dependent manner. This study identifies FoxM1 as a critical regulator of mammary differentiation with significant implications for the development of aggressive breast cancers.
| S-EPMC3401379 | biostudies-literature
Project description:Spinal cord injury remains a scientific and therapeutic challenge with great cost to individuals and society. The goal of research in this field is to find a means of restoring lost function. Recently we have seen considerable progress in understanding the injury process and the capacity of CNS neurons to regenerate, as well as innovations in stem cell biology. This presents an opportunity to develop effective transplantation strategies to provide new neural cells to promote the formation of new neuronal networks and functional connectivity. Past and ongoing clinical studies have demonstrated the safety of cell therapy, and preclinical research has used models of spinal cord injury to better elucidate the underlying mechanisms through which donor cells interact with the host and thus increase long-term efficacy. While a variety of cell therapies have been explored, we focus here on the use of neural progenitor cells obtained or derived from different sources to promote connectivity in sensory, motor and autonomic systems.
| S-EPMC8384139 | biostudies-literature
Project description:Sulf2a belongs to the Sulf family of extracellular sulfatases which selectively remove 6-O-sulfate groups from heparan sulfates, a critical regulation level for their role in modulating the activity of signalling molecules. Data presented here define Sulf2a as a novel player in the control of Sonic Hedgehog (Shh)-mediated cell type specification during spinal cord development. We show that Sulf2a depletion in zebrafish results in overproduction of V3 interneurons at the expense of motor neurons and also impedes generation of oligodendrocyte precursor cells (OPCs), three cell types that depend on Shh for their generation. We provide evidence that Sulf2a, expressed in a spatially restricted progenitor domain, acts by maintaining the correct patterning and specification of ventral progenitors. More specifically, Sulf2a prevents Olig2 progenitors to activate high-threshold Shh response and, thereby, to adopt a V3 interneuron fate, thus ensuring proper production of motor neurons and OPCs. We propose a model in which Sulf2a reduces Shh signalling levels in responding cells by decreasing their sensitivity to the morphogen factor. More generally, our work, revealing that, in contrast to its paralog Sulf1, Sulf2a regulates neural fate specification in Shh target cells, provides direct evidence of non-redundant functions of Sulfs in the developing spinal cord.
| S-EPMC7794431 | biostudies-literature