Retinoic Acid Functions as a Key GABAergic Differentiation Signal in the Basal Ganglia

Stanford University, United States of America
PLoS Biology (Impact Factor: 9.34). 04/2011; 9(4):e1000609. DOI: 10.1371/journal.pbio.1000609
Source: PubMed


Although retinoic acid (RA) has been implicated as an extrinsic signal regulating forebrain neurogenesis, the processes regulated by RA signaling remain unclear. Here, analysis of retinaldehyde dehydrogenase mutant mouse embryos lacking RA synthesis demonstrates that RA generated by Raldh3 in the subventricular zone of the basal ganglia is required for GABAergic differentiation, whereas RA generated by Raldh2 in the meninges is unnecessary for development of the adjacent cortex. Neurospheres generated from the lateral ganglionic eminence (LGE), where Raldh3 is highly expressed, produce endogenous RA, which is required for differentiation to GABAergic neurons. In Raldh3⁻/⁻ embryos, LGE progenitors fail to differentiate into either GABAergic striatal projection neurons or GABAergic interneurons migrating to the olfactory bulb and cortex. We describe conditions for RA treatment of human embryonic stem cells that result in efficient differentiation to a heterogeneous population of GABAergic interneurons without the appearance of GABAergic striatal projection neurons, thus providing an in vitro method for generation of GABAergic interneurons for further study. Our observation that endogenous RA is required for generation of LGE-derived GABAergic neurons in the basal ganglia establishes a key role for RA signaling in development of the forebrain.

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    • "The patterning events that define A–P and D–V identities in vivo can be mimicked performing ES cell differentiation in a minimal medium devoid of growth factors and morphogens. The effects of RA, BMPs, Wnts, FGFs, and Sonic Hedgehog (SHH) on the identity of neurons generated by ES cells have been described (Watanabe et al., 2005; Eiraku et al., 2008; Gaspard et al., 2008; Chatzi et al., 2011). Addition of caudalizing signals, such as RA or FGF2 can promote a spinal cord identity and subsequent production of motor neurons (Wichterle et al., 2002), whereas addition of Wnt and Nodal antagonists promotes production of telencephalic progenitors (Watanabe et al., 2005). "
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    ABSTRACT: Embryonic stem (ES) cells are becoming a popular model of in vitro neurogenesis, as they display intrinsic capability to generate neural progenitors that undergo the known steps of in vivo neural development. These include the acquisition of distinct regional fates, which depend on the growth factors and signals that are present in the culture medium. The control of the intracellular signaling that is active at different steps of ES cell neuralization, even when cells are cultured in chemically defined medium, is complicated by the endogenous production of growth factors. However, this endogenous production has been poorly investigated so far. To address this point, we performed a high-throughput analysis of the expression of morphogens during mouse ES cell neuralization in minimal medium. We found that during their neuralization, ES cells increased the expression of members of Wnt, FGF and BMP families. Conversely, the expression of Activin/Nodal and Shh ligands was low in early steps of neuralization. In this experimental condition, neural progenitors and neurons generated by ES cells expressed a gene expression profile that was consistent with a mid-brain identity. We found that endogenous BMP and Wnt signaling, but not FGF signaling, synergistically affected ES cell neural patterning, by turning off a profile of dorsal/telencephalic gene expression. Double BMP and Wnt inhibition allowed neuralized ES cells to sequentially activate key genes of cortical differentiation. Our findings are consistent with a novel synergistic effect of Wnt and BMP endogenous signaling of ES cells in inhibiting a cortical differentiation program. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014
    Full-text · Article · Jan 2015 · Developmental Neurobiology
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    • "[Dietary vitamin A, through its metabolite retinoic acid] converts glutamate to the inhibitory neurotransmitter GABA… [in a deficiency, it] greatly diminished GABA… Deficiencies in GABAergic neurons [are]… associated with… Huntington's disease, autism, schizophrenia, and epilepsy (Bravo et al., 2011; Chatzi et al., 2011). "
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    ABSTRACT: Background: Medicine devotes its primary focus to understanding change, from cells to network relationships; observations of non-linearity are inescapable. Recent events provide extraordinary examples of major non-linear surprises within the societal system: human genome-from anticipated 100,000+ genes to only 20,000+; junk DNA-initially ignored but now proven to control genetic processes; economic reversals-bursting of bubbles in technology, housing, finance; foreign wars; relentless rise in obesity, neurodegenerative diseases. There are two attributes of systems science that are especially relevant to this research: One—it offers a method for creating a structural context with a guiding path to pragmatic knowledge; and, two—it gives pre-eminence to sensory input capable to register, evaluate, and react to change.Materials/Methods: Public domain records of change, during the last 50 years, have been studied in the context of systems science, the dynamic systems model, and various cycles.Results/Conclusions: Change is dynamic, ever-present, never isolated, and of variable impact; it reflects innumerable relationships among contextual systems; change can be perceived as risk or uncertainty depending upon how the assessment is made; risk is quantifiable by sensory input and generates a degree of rational optimism; uncertainty is not quantifiable and evokes fear; trust is key to sharing risk; the measurable financial credit can be a proxy for societal trust; expanding credit dilutes trust; when a credit bubble bursts, so will trust; absence of trust paralyzes systems' relationships leading to disorganized complexity which prevents value creation and heightens the probability of random events; disappearance of value, accompanied by chaos, threatens all systems. From personal health to economic sustainability and collective rationality, most examined components of the societal system were found not to be optimized and trust was not in evidence.
    Full-text · Article · Mar 2014 · Frontiers in Computational Neuroscience
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    • "Investigation of an ethylnitrosoureainduced Rdh10 mutant with reduced RA synthesis in the meninges was reported to exhibit reduced radial expansion of forebrain cortical neurons at E14.5 (Siegenthaler et al., 2009). However, RA-rescued Raldh2À/À embryos that lack meningeal RA synthesis do not exhibit a defect in forebrain cortical expansion (Chatzi et al., 2011). Here, a strain of Rdh10À/À null mice was generated, and the role of RA in early brain patterning and forebrain cortical expansion was further examined. "
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    ABSTRACT: Background: Retinoic acid (RA) signaling controls patterning and neuronal differentiation within the hindbrain, but forebrain RA function remains controversial. RA is produced from metabolism of retinol to retinaldehyde by retinol dehydrogenase (RDH), followed by metabolism of retinaldehyde to RA by retinaldehyde dehydrogenase (RALDH). Previous studies on Raldh2-/- and Raldh3-/- mice demonstrated an RA requirement for γ-aminobutyric acid (GABA)ergic and dopaminergic differentiation in forebrain basal ganglia, but no RA requirement was observed during early forebrain patterning or subsequent forebrain cortical expansion. However, other studies suggested that RA controls forebrain patterning, and analysis of ethylnitrosourea-induced Rdh10 mutants suggested that RA synthesized in the meninges stimulates forebrain cortical expansion. Results: We generated Rdh10-/- mouse embryos that lack RA activity early in the head and later in the meninges. We observed defects in hindbrain patterning and eye RA signaling, but early forebrain patterning was unaffected. Retinaldehyde treatment of Rdh10-/- embryos from E7-E9 rescues a cranial skeletal defect, resulting in E14.5 embryos lacking meningeal RA activity but maintaining normal forebrain shape and cortical expansion. Conclusions: Rdh10-/- embryos demonstrate that RA controls hindbrain but not early forebrain patterning, while studies on retinaldehyde-rescued Rdh10-/- embryos show that meningeal RA synthesis is unnecessary to stimulate forebrain cortical expansion.
    Full-text · Article · Sep 2013 · Developmental Dynamics
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