Identification of the Neogenin-Binding Site on the Repulsive Guidance Molecule A

Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the chick retinotectal system. RGMa, one of the 3 isoforms found in mammals, is involved in laminar patterning, cephalic neural tube closure, axon guidance, and inhibition of axonal regeneration. In addition to its roles in the nervous system, RGMa plays a role in enhancing helper T-cell activation. Binding of RGM to its receptor, neogenin, is considered necessary to transduce these signals; however, information on the binding of RGM to neogenin is limited. Using co-immunoprecipitation studies, we have identified that the RGMa region required for binding to neogenin contains amino acids (aa) 259–295. Synthesized peptide consisting of aa 284–293 directly binds to the extracellular domain (ECD) of recombinant neogenin, and addition of this peptide inhibits RGMa-induced growth cone collapse in mouse cortical neurons. Thus, we propose that this peptide is a promising lead in finding reagents capable of inhibiting RGMa signaling

Activated Microglia Inhibit Axonal Growth through RGMa

By causing damage to neural networks, spinal cord injuries (SCI) often result in severe motor and sensory dysfunction. Functional recovery requires axonal regrowth and regeneration of neural network, processes that are quite limited in the adult central nervous system (CNS). Previous work has shown that SCI lesions contain an accumulation of activated microglia, which can have multiple pathophysiological influences. Here, we show that activated microglia inhibit axonal growth via repulsive guidance molecule a (RGMa). We found that microglia activated by lipopolysaccharide (LPS) inhibited neurite outgrowth and induced growth cone collapse of cortical neurons in vitro—a pattern that was only observed when there was direct contact between microglia and neurons. After microglia were activated by LPS, they increased expression of RGMa; however, treatment with RGMa-neutralizing antibodies or transfection of RGMa siRNA attenuated the inhibitory effects of microglia on axonal outgrowth. Furthermore, minocycline, an inhibitor of microglial activation, attenuated the effects of microglia and RGMa expression. Finally, we examined whether these in vitro patterns could also be observed in vivo. Indeed, in a mouse SCI model, minocycline treatment reduced the accumulation of microglia and decreased RGMa expression after SCI, leading to reduced dieback in injured corticospinal tracts. These results suggest that activated microglia play a major role in inhibiting axon regeneration via RGMa in the injured CNS

The role of leptin in the central nervous system remyelination

Leptin is identified as a mouse obesity gene, which is also preserved in humans. Leptin receptor is highly expressed in the hypothalamus relative to other tissues; therefore, the function of leptin is mainly attributed to hypothalamic control of food intake and body weight. Although the expression of leptin receptors is not limited to the hypothalamus but is also present in other regions of the central nervous system (CNS), such as the spinal cord, the functions of leptin and leptin receptor in the CNS have not been fully clarified. In this research highlight, we focus on the novel function of leptin in CNS remyelination in pathologic conditions, such as the demyelination mouse model. Because remyelination is a crucial process for repair of neuronal networks after injury and wound healing, knowledge of the underlying molecular mechanism of remyelination is useful to establish a therapeutic strategy against demyelinating diseases. We only revealed the role of leptin in remyelination at a histological level; however, a behavioral analysis and evidence of the beneficial effect of leptin for humans may add to knowledge of the effect of leptin on remyelination function

Publisher Correction: Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging

The original version of this Article had an incorrect Article number of 1, an incorrect Volume of 5 and an incorrect Publication year of 2019. These errors have now been corrected in the PDF and HTML versions of the Article

Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging

Epigenetic silencing of Lgr5 in aged organoids To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice, and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice. Our results suggest that organoids derived from aged animals could be a powerful research tool for investigating the molecular mechanisms underlying stem cell aging and for development of some form of anti-aging intervention, thus contributing to prolongation of healthy life expectancy

Extracellular Lactate Dehydrogenase A Release From Damaged Neurons Drives Central Nervous System Angiogenesis

Angiogenesis, a prominent feature of pathology, is known to be guided by factors secreted by living cells around a lesion. Although many cells are disrupted in a response to injury, the relevance of degenerating cells in pathological angiogenesis is unclear. Here, we show that the release of lactate dehydrogenase A (LDHA) from degenerating neurons drives central nervous system (CNS) angiogenesis. Silencing neuronal LDHA expression suppressed angiogenesis around experimental autoimmune encephalomyelitis (EAE)- and controlled cortical impact-induced lesions. Extracellular LDHA-mediated angiogenesis was dependent on surface vimentin expression and vascular endothelial growth factor receptor (VEGFR) phosphorylation in vascular endothelial cells. Silencing vimentin expression in vascular endothelial cells prevented angiogenesis around EAE lesions and improved survival in a mouse model of glioblastoma. These results elucidate novel mechanisms that may mediate pathologic angiogenesis and identify a potential molecular target for the treatment of CNS diseases involving angiogenesis