Meteorin promotes the formation of GFAP-positive glia via activation of the Jak-STAT3 pathway

Abstract

SummaryMeteorin is an orphan ligand which has been previously reported to control neuritogenesis and angiogenesis, as well as gliogenesis.However, the precise function of this factor in CNS development and the underlying molecular mechanisms are poorly understood. Here, we demonstrate that meteorin is involved in GFAP-positive glial differentiation through activation of the Jak-STAT3 pathway, by using neurosphere and retinal explant culture systems. During embryonic brain development, meteorin is highly expressed in neural stem and radial glia cells of the ventricular zone and immature neurons outside the ventricular zone but its expression disappears spontaneously as development proceeds except in GFAP-positive astrocytes. In cultured neurospheres, meteorin activates STAT3, and in turn increases the transcriptional activity of GFAP by enhancing the binding of STAT3 to the promoter. By meteorin stimulation, differentiating neurospheres show increased numbers of GFAP-positive cells, but the effect is abrogated by a blockade of the Jak-STAT3 pathway using either a Jak inhibitor or STAT3 siRNA. Furthermore, we expand our findings to the retina, and show that meteorin increases GFAP expression in Müller glia. Together, our results suggest that meteorin promotes GFAP-positive glia formation by mediating the Jak-STAT3 signaling pathway during both cortical stem cell differentiation and retinal glia development.

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…However, the cellular receptor(s) for meteorin are still unknown. It has been reported that meteorin acts through the Jak‐STAT3 pathway to promote glial differentiation in neural stem cells (Lee, Han, Lee, Park, & Kim, 2010). However, exogenous treatment of astrocytes with meteorin did not activate the same pathway (Lee et al, 2015).…”

Meteorin is a Chemokinetic Factor in Neuroblast Migration and Promotes Stroke-Induced Striatal Neurogenesis

“…In the adult mouse brain, METRN is detected in ubiquitously distributed astrocytes, Bergmann glia, and a few discrete neuronal populations (Nishino et al, 2004;Jorgensen et al, 2009). Meteorin has been implicated in the regulation of axonal extension and glial cell differentiation (Nishino et al, 2004;Lee et al, 2010) and in angiogenesis (Park et al, 2008). Additionally, administration of METRN protects striatal neurons from excitotoxicity caused by quinolinic acid in vivo (Jorgensen et al, 2011).…”

Meteorin is upregulated in reactive astrocytes and functions as a negative feedback effector in reactive gliosis

“…Primary NSCs were cultured from E13.5 mouse embryos, as described previously (12). Briefly, embryos were dissected from pregnant female mice (Samtako) and neurospheres were allowed to form in complete neurobasal medium (Invitrogen Life Technologies) containing 2% B27 (Invitrogen Life Technologies), human epidermal growth factor (20 ng/ml, R&D Systems, Minneapolis, MN, USA), and basic fibroblast growth factor (10 ng/ml, Invitrogen Life Technologies) for 4 days, by plating neuroepithelial cells on non-coated culture dishes.…”

“…The predominant source of meteorin in the adult brain are astrocytes, and meteorin is known to promote glial cell differentiation and the expression of GFAP in NSCs (12,17); therefore, the present study aimed to demonstrate that meteorin was involved in the reactive gliosis process. The expression levels of meteorin were analyzed in reactive astrocytes from a photothrombotic (PT) ischemia mouse model, as well as following stimulation of transforming growth factor (TGF)-β, which led to the activation of astrocytes in vitro .…”

“…In the developing rodent CNS, meteorin is highly expressed in the neuroepithelium and remains in subpopulations of the glia, including the cortical astrocytes, following completion of CNS development (11,12). Our previous study reported that meteorin promotes glial differentiation in neural stem cells (NSCs) via activation of the janus kinase (Jak)-signal transducer and activator of trascription 3 (STAT3) signaling pathway (12), and that astrocytic meteorin promotes the maturation of the BBB by stimulating endothelial cells (13). Regarding its involvement in CNS pathologies, previous studies have reported on the neuroprotective effects of meteorin in rat models of neuropathic pain and in quinolic acid-induced neuropathology (14,15).…”