Kim EJ, Battiste J, Nakagawa Y, Johnson JEAscl1 (Mash1) lineage cells contribute to discrete cell populations in CNS architecture. Mol Cell Neurosci 38:595-606

Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 08/2008; 38(4):595-606. DOI: 10.1016/j.mcn.2008.05.008


Ascl1 (previously Mash1) is a bHLH transcription factor essential for neuronal differentiation and specification in the nervous system. Although it has been studied for its role in several neural lineages, the full complement of lineages arising from Ascl1 progenitor cells remains unknown. Using an inducible Cre-flox genetic fate-mapping strategy, Ascl1 lineages were determined throughout the brain. Ascl1 is present in proliferating progenitor cells but these cells are actively differentiating as evidenced by rapid migration out of germinal zones. Ascl1 lineage cells contribute to distinct cell types in each major brain division: the forebrain including the cerebral cortex, olfactory bulb, hippocampus, striatum, hypothalamus, and thalamic nuclei, the midbrain including superior and inferior colliculi, and the hindbrain including Purkinje and deep cerebellar nuclei cells and cells in the trigeminal sensory system. Ascl1 progenitor cells at early stages in each CNS region preferentially become neurons, and at late stages they become oligodendrocytes. In conclusion, Ascl1-expressing progenitor cells in the brain give rise to multiple, but not all, neuronal subtypes and oligodendrocytes depending on the temporal and spatial context, consistent with a broad role in neural differentiation with some subtype specification.

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    • "In VEGF-C-treated cells, the expression of NSC markers such as Notch1/2 (Ables et al., 2010), Hes5 (Imayoshi et al., 2013), Ctnnb1(b1-catenin) (Lie et al., 2005), Bmpr1 (bone morphogenetic protein receptor) (Mira et al., 2010), Mhi1/2 (Mushashi1/2) (Okano et al., 2005), Bmi-1 (Fasano et al., 2009), and Rest (Abrajano et al., 2010) are downregulated whereas the expression of progenitor cell markers Ascl1 (Kim et al., 2008; Lugert et al., 2012), Sox21 (Matsuda et al., 2012), and Numb (Aguirre et al., 2010; Petersen et al., 2002) are upregulated (Figure S2B; Table S2B). To confirm the effect of VEGF-C on cell cycle progression, we analyzed the cell cycle activity of Vegfr3 YFP cells. "
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    ABSTRACT: Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR) 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs), VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Cell Reports
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    • "Cerebellar Ascl1/Mash1+ precursors give rise to PCs and to all GABAergic interneurons (Kim et al., 2008; Grimaldi et al., 2009; Sudarov et al., 2011). Precursors expressing neurogenin 1 (Neurog1) become PCs or cortical GABA interneurons (Kim et al., 2008; Lundell et al., 2009). Neurog2+ precursors give rise to PCs and GABAergic CN neurons, including presumptive nucleo-olivary neurons and interneurons (Florio et al., 2012). "
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    ABSTRACT: The Purkinje cells (PC's) of the cerebellar cortex are subdivided into multiple different molecular phenotypes that form an elaborate array of parasagittal stripes. This array serves as a scaffold around which afferent topography is organized. The ways in which cerebellar interneurons may be restricted by this scaffolding are less well-understood. This review begins with a brief survey of cerebellar topography. Next, it reviews the development of stripes in the cerebellum with a particular emphasis on the embryological origins of cerebellar interneurons. These data serve as a foundation to discuss the hypothesis that cerebellar compartment boundaries also restrict cerebellar interneurons, both excitatory [granule cells, unipolar brush cells (UBCs)] and inhibitory (e.g., Golgi cells, basket cells). Finally, it is proposed that the same PC scaffold that restricts afferent terminal fields to stripes may also act to organize cerebellar interneurons.
    Full-text · Article · Dec 2012 · Frontiers in Neural Circuits
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    • "Considerable controversy exists concerning the degree to which NPs retain in vitro the positional information acquired in their region of origin. Some studies indicated that NPs maintained their regional specification even after several passages in vitro as neurospheres [5], [9], [45], [46], while others reported a progressive loss of regional identity due to the downregulation of dorsal and ventral markers in culture [29], [47]. It should be mentioned that different properties of NPs depend on the culture conditions used, even at early passages [48], or on the species of origin, e.g. "
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    ABSTRACT: During neural development, spatially regulated expression of specific transcription factors is crucial for central nervous system (CNS) regionalization, generation of neural precursors (NPs) and subsequent differentiation of specific cell types within defined regions. A critical role in dopaminergic differentiation in the midbrain (MB) has been assigned to the transcription factor Nurr1. Nurr1 controls the expression of key genes involved in dopamine (DA) neurotransmission, e.g. tyrosine hydroxylase (TH) and the DA transporter (DAT), and promotes the dopaminergic phenotype in embryonic stem cells. We investigated whether cells derived from different areas of the mouse CNS could be directed to differentiate into dopaminergic neurons in vitro by forced expression of the transcription factor Nurr1. We show that Nurr1 overexpression can promote dopaminergic cell fate specification only in NPs obtained from E13.5 ganglionic eminence (GE) and MB, but not in NPs isolated from E13.5 cortex (CTX) and spinal cord (SC) or from the adult subventricular zone (SVZ). Confirming previous studies, we also show that Nurr1 overexpression can increase the generation of TH-positive neurons in mouse embryonic stem cells. These data show that Nurr1 ability to induce a dopaminergic phenotype becomes restricted during CNS development and is critically dependent on the region of NPs derivation. Our results suggest that the plasticity of NPs and their ability to activate a dopaminergic differentiation program in response to Nurr1 is regulated during early stages of neurogenesis, possibly through mechanisms controlling CNS regionalization.
    Full-text · Article · Dec 2012 · PLoS ONE
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