Dlx1 and Mash1 Transcription Factors Control MGE and CGE Patterning and Differentiation through Parallel and Overlapping Pathways

Department of Psychiatry and the Nina Ireland Laboratory of Developmental Neurobiology, University of California at San Francisco, San Francisco, CA 94158-2324, USA.
Cerebral Cortex (Impact Factor: 8.67). 05/2009; 19 Suppl 1(Suppl. 1):i96-106. DOI: 10.1093/cercor/bhp045
Source: PubMed Central


Here we define the expression of ∼100 transcription factors (TFs) in progenitors and neurons of the developing mouse medial
and caudal ganglionic eminences, anlage of the basal ganglia and pallial interneurons. We have begun to elucidate the transcriptional
hierarchy of these genes with respect to the Dlx homeodomain genes, which are essential for differentiation of most γ-aminobutyric acidergic projection neurons of the basal
ganglia. This analysis identified Dlx-dependent and Dlx-independent pathways. The Dlx-independent pathway depends in part on the function of the Mash1 basic helix-loop-helix (b-HLH) TF. These analyses define core transcriptional components that differentially specify the
identity and differentiation of the globus pallidus, basal telencephalon, and pallial interneurons.

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Available from: Gregory Brian Potter, Feb 18, 2014
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    • "The use of transcription factor expression to classify arkypallidal and prototypic neurons has relevance for understanding the developmental origins of these GPe cell types. Indeed, Nkx2-1 is expressed throughout the proliferative ventricular zone of the MGE in the embryonic subpallium/ventral telencephalon (Butt et al., 2005; Flames et al., 2007; Long et al., 2009; Nó brega-Pereira et al., 2010; Sussel et al., 1999), suggesting that the MGE is the progenitor domain of origin of most GPe neurons (Flandin et al., 2010; Nó brega-Pereira et al., 2010; Sussel et al., 1999). However, as much as one quarter of all GPe cells are generated outside the Nkx2-1+ MGE (Nó brega-Pereira et al., 2010). "
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    ABSTRACT: Transcriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Neuron
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    • "Dlx1/2-null mutants have a severe deficit in survival and migration resulting in a 70% reduction of these cells in the neocortex (Anderson et al., 1997; Sussel et al., 1999). Working in concert with Dlx1/2, the proneural gene Mash1 is expressed in the subpallial SVZ and is required for the production and differentiation of GABAergic interneurons (Casarosa et al., 1999; Petryniak et al., 2007; Long et al., 2009). Similar to Dlx1/2, elimination of Mash1 expression results in a substantial decrease in GABAergic neocortical interneurons (Casarosa et al., 1999). "
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    ABSTRACT: Inhibitory GABA (γ-aminobutyric acid)-ergic interneurons are a vital component of the neocortex responsible for shaping its output through a variety of inhibitions. Consisting of many flavors, interneuron subtypes are predominantly defined by their morphological, physiological, and neurochemical properties that help to determine their functional role within the neocortex. During development, these cells are born in the subpallium where they then tangentially migrate over long distances before being radially positioned to their final location in the cortical laminae. As development progresses into adolescence, these cells mature and form chemical and electrical connections with both glutamatergic excitatory neurons and other interneurons ultimately establishing the cortical network. The production, migration, and organization of these cells are determined by vast array of extrinsic and intrinsic factors that work in concert in order to assemble a proper functioning cortical inhibitory network. Failure of these cells to undergo these processes results in abnormal positioning and cortical function. In humans, this can bring about several neurological disorders including schizophrenia, epilepsy, and autism spectrum disorders. In this article, we will review previous literature that has revealed the framework for interneuron neurogenesis and migratory behavior as well as discuss recent findings that aim to elucidate the spatial and functional organization of interneurons within the neocortex.
    Full-text · Article · Oct 2013 · Frontiers in Cellular Neuroscience
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    • "The expression pattern of Dact1 in the E14.5 cortex is reminiscent of the distribution of tangentially migrating immature interneurons that are derived from the GE's (Figure 1A; as indicated by arrowheads). This is consistent with previous findings that Dlx1 and Dlx2 repress mRNA expression of Dact1 in the ganglionic eminences [33] and that Dact1 gene expression increases in GE-derived interneurons during their migration to the cortex between E13.5 and E15.5 [27], [28]. Nonetheless, Dact1 continues to be expressed at E18.5, far beyond the developmental peak in tangential migration of immature interneurons. "
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    ABSTRACT: Synaptogenesis has been extensively studied along with dendritic spine development in glutamatergic pyramidal neurons, however synapse development in cortical interneurons, which are largely aspiny, is comparatively less well understood. Dact1, one of 3 paralogous Dact (Dapper/Frodo) family members in mammals, is a scaffold protein implicated in both the Wnt/β-catenin and the Wnt/Planar Cell Polarity pathways. We show here that Dact1 is expressed in immature cortical interneurons. Although Dact1 is first expressed in interneuron precursors during proliferative and migratory stages, constitutive Dact1 mutant mice have no major defects in numbers or migration of these neurons. However, cultured cortical interneurons derived from these mice have reduced numbers of excitatory synapses on their dendrites. We selectively eliminated Dact1 from mouse cortical interneurons using a conditional knock-out strategy with a Dlx-I12b enhancer-Cre allele, and thereby demonstrate a cell-autonomous role for Dact1 during postsynaptic development. Confirming this cell-autonomous role, we show that synapse numbers in Dact1 deficient cortical interneurons are rescued by virally-mediated re-expression of Dact1 specifically targeted to these cells. Synapse numbers in these neurons are also rescued by similarly targeted expression of the Dact1 binding partner Dishevelled-1, and partially rescued by expression of Disrupted in Schizophrenia-1, a synaptic protein genetically implicated in susceptibility to several major mental illnesses. In sum, our results support a novel cell-autonomous postsynaptic role for Dact1, in cooperation with Dishevelled-1 and possibly Disrupted in Schizophrenia-1, in the formation of synapses on cortical interneuron dendrites.
    Full-text · Article · Jun 2013 · PLoS ONE
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