Astroglia‐derived retinoic acid is a key factor in glia‐induced neurogenesis

Abstract

Astroglial cells are essential components of the neurogenic niches within the central nervous system. Emerging evidence suggests that they are among the key regulators of postnatal neurogenesis. Although astrocytes have been demonstrated to possess the potential to instruct stem cells to adopt a neuronal fate, little is known about the nature of the glia-derived instructive signals. Here we propose that all-trans retinoic acid, one of the most powerful morphogenic molecules regulating neuronal cell fate commitment, may be one of the glia-derived factors directing astroglia-induced neurogenesis. According to data obtained from several complementary approaches, we show that cultured astrocytes express the key enzyme mRNAs of retinoic acid biosynthesis and actively produce all-trans retinoic acid. We show that blockage of retinoic acid signaling by the pan-RAR antagonist AGN193109 prevents glia-induced neuron formation by noncommitted stem cells. Therefore, we provide strong in vitro evidence for retinoic acid action in astroglia-induced neuronal differentiation.

Astrocytes as a regulated source of retinoic acid for the brain

“…It has been previously demonstrated that RALDH enzymes are expressed in primary rodent cultured astrocytes (Kornyei et al, 2007;McCaffery et al, 2004;Wang et al, 2011). This study, however, demonstrates that this expression is not reflected in the majority of astrocytes in vivo either in the mouse or in the human.…”

“…This study, however, demonstrates that this expression is not reflected in the majority of astrocytes in vivo either in the mouse or in the human. Thus, although it has been previously proposed that astrocytes in the rodent may provide RA for neural progenitors in the brain (Kornyei et al, 2007) and for neurons in the hippocampus (Wang et al, 2011), it is unlikely that these are a major source of RA under normal circumstances. The low levels of RALDH protein and mRNA in the adult mouse brain are corroborated by the weak in situ hybridization signal evident from results documented in the Allen Brain Atlas (http://mouse.brainmap.org/).…”

“…1H,I). As RA synthesized by astrocytes has been suggested to regulate birth of new neurons from adult brain progenitors (Kornyei et al, 2007), the hippocampus and subventricular zone of the forebrain, which contain neurogenic regions, were also investigated. None of the GFAP-positive cells in these regions express RALDHs (Supp.…”

“…A transgenic RA reporter mouse in which a RA response element (RARE) drives a lacZ reporter (Rossant et al, 1991) has been previously used to show RA signals in a proportion of glia in the hippocampus and cortex (Kornyei et al, 2007). Double labeling with GFAP and lacZ shows that some glia are responsive to RA ( Fig.…”

“…A number of reports have demonstrated that cultured astrocytes express the RARs, RA synthetic enzymes retinol dehydrogenases, and retinaldehyde dehydrogenases (RALDHs) (Chattopadhyay and Brown, 2001;Kane et al, 2008;McCaffery et al, 2004;Wang et al, 2011) and can generate RA (Wuarin et al, 1990). Further, it has been proposed that astrocytes may be a source of RA to regulate neurogenesis in the adult brain (Kornyei et al, 2007). This report, however, finds that the protein levels of the RALDH enzymes, essential to produce RA in vivo, are too low to be detectable.…”