CoREST/LSD1 Control the Development of Pyramidal Cortical Neurons

Fuentes, Patricio; Cánovas, José Luis; Berndt, F. Andrés; Noctor, Stephen C.; Kukuljan, Manuel

doi:10.1093/cercor/bhr218

Cited by 80 publications

(95 citation statements)

References 31 publications

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“…CoREST forms a complex with REST and represses target gene expression by recruiting chromatin-binding proteins and histone modifiers (274). In the developing cerebral cortex, CoREST and REST regulate Dcx gene expression, thereby regulating neuronal migration (84,202). Epigenetic regulation of polarity genes may fine-tune gene expression in a time-and space-dependent manner.…”

Section: Regulation Of Gene Expressionmentioning

confidence: 99%

Extracellular and Intracellular Signaling for Neuronal Polarity

Namba

Funahashi

Nakamuta

et al. 2015

Physiological Reviews

113

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Neurons are one of the highly polarized cells in the body. One of the fundamental issues in neuroscience is how neurons establish their polarity; therefore, this issue fascinates many scientists. Cultured neurons are useful tools for analyzing the mechanisms of neuronal polarization, and indeed, most of the molecules important in their polarization were identified using culture systems. However, we now know that the process of neuronal polarization in vivo differs in some respects from that in cultured neurons. One of the major differences is their surrounding microenvironment; neurons in vivo can be influenced by extrinsic factors from the microenvironment. Therefore, a major question remains: How are neurons polarized in vivo? Here, we begin by reviewing the process of neuronal polarization in culture conditions and in vivo. We also survey the molecular mechanisms underlying neuronal polarization. Finally, we introduce the theoretical basis of neuronal polarization and the possible involvement of neuronal polarity in disease and traumatic brain injury.

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Section: Regulation Of Gene Expressionmentioning

confidence: 99%

Extracellular and Intracellular Signaling for Neuronal Polarity

Namba

Funahashi

Nakamuta

et al. 2015

Physiological Reviews

113

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“…CoREST (also known as Rcor2 -Mouse Genome Informatics) is a common epigenetic repressor that is widely expressed in the developing brain (Fuentes et al, 2012;Tontsch et al, 2001) and is…”

Section: Inhibitory Role Of Corest In Da Gene Expression By Protein Imentioning

confidence: 99%

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Rhee

et al. 2014

Development

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Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-associated disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Coexpression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a positive cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoRESTHdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.KEY WORDS: Foxa2, Nurr1, Midbrain dopamine neuron, Development, Neural precursor cell, Epigenetic control, CoREST, Hdac, Mouse INTRODUCTIONMidbrain dopamine (mDA) neurons play important roles in voluntary movement, emotion and reward-based behaviors. Dysfunction or degeneration of this neuronal subtype is related to major neuropsychiatric disorders such as Parkinson's disease (PD), schizophrenia and drug addiction. Owing to the pathophysiological implications, mDA neurons are the most extensively studied cells. A molecular understanding of mDA neuron development is of high clinical interest as replacing this cell population in diseased brains is considered to be one of the most promising therapeutic approaches for PD (Deierborg et al., 2008;Morizane et al., 2008). In addition, developmental information can be exploited to establish optimal bioassays for mDA neuron-related disorders. mDA neurons arise from floor plate cells at the ventral midline of the embryonic midbrain (Bonilla et al., 2008;Ono et al., 2007). Sonic hedgehog (Shh), secreted initially by the notochord and later by floor plate cells, induces expression of forkhead family of winged-helix transcription factor 2 (Foxa2; also known as hepatocyte nuclear factor 3 beta), in the midbrain floor plate cells [mouse embryonic day (E) 8.5] (Ang et al., 1993;Monaghan et al., 1993;Placzek, 1995;Sasaki and Hogan, 1994;Sasaki et al., 1997). Foxa2 acts as a master regulator to induce expression of developmental factors specifying mDA neuron precursors such as Nurr1, Pitx3, Lmx1a, Msx1, neurogenin 2 and Mash1 (Ascl1 -Mouse Genome Informatics) (Ang, 2009;Ferri et al., 2007;Kittappa et al., 2007;Lee et al., 2010;Metzakopian et al., 2012). The early inductive role of Foxa2 is probably achieved by cooperation with the Wnt-Lmx1a/b regulatory loop from the isthmic organizer (Chung et al., 2009;Naka...

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“…Previous studies have shown that LSD1 influences cell proliferation, is prosurvival, 52,53 aids in neurite morphogenesis, 54 and promotes neural differentiation and development. 55 It has also been shown that the inhibition of LSD1 by tranylcypromine modulates neural stem cell proliferation in the mouse brain 53 and changes zebrafish lateral line neuromast development. 56 Interestingly, the present findings indicate that tranylcypromine also significantly benefited cell survival in the mammalian CNS.…”

Section: Discussionmentioning

confidence: 99%

Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity

Tsutsumi

Iwao

Hayashi

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Tsutsumi T, Iwao K, Hayashi H, et al. Potential neuroprotective effects of an LSD1 inhibitor in retinal ganglion cells via p38 MAPK activity. Invest Ophthalmol Vis Sci. 2016;57:6461-6473. DOI:10.1167/ iovs.16-19494 PURPOSE. The epigenetic mechanisms associated with ocular neurodegenerative diseases remain unclear. The present study aimed to determine the role of lysine-specific demethylase 1 (LSD1), which represses transcription by removing the methyl group from methylated lysine 4 of histone H3, in retinal ganglion cell (RGC) survival, and to investigate the details of the neuroprotective mechanism of tranylcypromine, a major LSD1 inhibitor. METHODS.The authors evaluated whether tranylcypromine contributes to neuronal survival following stress-induced damage using primary cultured rat RGCs and in vivo N-methyl-Daspartate (NMDA)-induced excitotoxicity. Additionally, the molecules associated with tranylcypromine treatment were assessed by microarray and immunoblot analysis. RESULTS.Tranylcypromine significantly suppressed neuronal cell death following glutamate neurotoxicity and oxidative stress. Microarray and immunoblot analyses revealed that p38 mitogen-activated protein kinase (MAPK)c was a key molecule involved in the neuroprotective mechanisms induced by tranylcypromine because the significant suppression of p38 MAPKc by glutamate was reversed by tranylcypromine. Moreover, although pharmacologic inhibition of the phosphorylation of the total p38 MAPKs interfered with neuroprotective effects of tranylcypromine, the specific inhibition of p38 MAPKa and p38 MAPKb did not influence RGC survival. This suggests that the non-p38 MAPKa/b isoforms have important roles in neuronal survival by tranylcypromine. Additionally, the intravitreal administration of tranylcypromine significantly saved RGC numbers in an in vivo glaucoma model employing NMDA-induced excitotoxicity.CONCLUSIONS. These findings indicate that tranylcypromine-induced transcriptional and epigenetic regulation modulated RGC survival via the promotion of p38 MAPKc activity. Therefore, pharmacologic treatments that suppress LSD1 activity may be a novel therapeutic strategy that can be used to treat neurodegenerative diseases.

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CoREST/LSD1 Control the Development of Pyramidal Cortical Neurons

Cited by 80 publications

References 31 publications

Extracellular and Intracellular Signaling for Neuronal Polarity

Extracellular and Intracellular Signaling for Neuronal Polarity

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity

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