Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants

Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA.
The Journal of Comparative Neurology (Impact Factor: 3.23). 09/2008; 510(1):79-99. DOI: 10.1002/cne.21772
Source: PubMed


Here we analyze the role of the Lhx6 lim-homeobox transcription factor in regulating the development of subsets of neocortical, hippocampal, and striatal interneurons. An Lhx6 loss-of-function allele, which expresses placental alkaline phosphatase (PLAP), allowed analysis of the development and fate of Lhx6-expressing interneurons in mice lacking this homeobox transcription factor. There are Lhx6+;Dlx+ and Lhx6-;Dlx+ subtypes of tangentially migrating interneurons. Most interneurons in Lhx6(PLAP/PLAP) mutants migrate to the cortex, although less efficiently, and exhibit defects in populating the marginal zone and superficial parts of the neocortical plate. By contrast, migration to superficial parts of the hippocampus is not seriously affected. Furthermore, whereas parvalbumin+ and somatostatin+ interneurons do not differentiate, NPY+ interneurons are present; we suggest that these NPY+ interneurons are derived from the Lhx6-;Dlx+ subtype. Striatal interneurons show deficits distinct from pallial interneurons, including a reduction in the NPY+ subtype. We provide evidence that Lhx6 mediates these effects through promoting expression of receptors that regulate interneuron migration (ErbB4, CXCR4, and CXCR7), and through promoting the expression of transcription factors either known (Arx) or implicated (bMaf, Cux2, and NPAS1) in controlling interneuron development.

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    • "These cells are bipotential precursors being able to terminally differentiate either into the GABAergic or cholinergic lineage. Terminal differentiation into GABAergic interneurons is dependent on sustained expression of LHX6 and thus representing a sort of “default” maturation pathway (Liodis et al., 2007; Zhao et al., 2008). Differentiation into the cholinergic lineage requires expression of LHX7 (also known as L3/LHX8) which induces expression of another LIM-homeodomain-transcription factor islet-1 (ISL1), which directly downregulates LHX6 expression (Fragkouli et al., 2009). "
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    ABSTRACT: Interneurons comprise a minority of the striatal neuronal population of roughly 5%. However, this heterogeneous population is of particular interest as it fulfills an important relay function in modulating the output of the only type of striatal projection neurons, i.e., the medium spiny neuron (MSN).One subtype of this heterogenous group, the cholinergic interneuron, is of particular scientific interest as there is a relevant body of evidence from animal models supporting its special significance in the disease process. The development of protocols for directed differentiation of human pluripotent stem cells (PSC) into striatal interneurons provides a unique opportunity to derive in vitro those cell types that are most severely affected in dystonia.In this review we first aim to give a concise overview about the normal function of striatal interneurons and their dysfunction in dystonia in order to identify the most relevant interneuronal subtype for the pathogenesis of dystonia. Secondly we demonstrate how knowledge about the embryonic development of striatal interneurons is of particular help for the development of differentiation protocols from PSC and by this depict potential ways of deriving in vitro disease models of dystonia. We furthermore address the question as to whether cell replacement therapies might represent a beneficial approach for the treatment of dystonia.
    Frontiers in Cellular Neuroscience 07/2014; 8:205. DOI:10.3389/fncel.2014.00205 · 4.29 Impact Factor
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    • "Among the genes affected by the deletion of Lhx6 in the dorsal forebrain was the Rho-GTPase protein Rac3. Since Lhx6 null mice show defects in the tangential migration of cortical interneurons (Liodis et al. 2007; Zhao et al. 2008), we hypothesized that this might be partially due to the lack of Rac3 protein in Lhx6 mutant interneurons. Nevertheless, Rac3 mutant mice have been reported not to have obvious defects in cortical interneuron migration (Corbetta et al. 2005), while Rac1-deficient mice show a 50% reduction of GABAergic neurons in the postnatal cortex (Vidaki et al. 2012). "
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    ABSTRACT: Cortical interneurons are characterized by extraordinary functional and morphological diversity. Although tremendous progress has been made in uncovering molecular and cellular mechanisms implicated in interneuron generation and function, several questions still remain open. Rho-GTPases have been implicated as intracellular mediators of numerous developmental processes such as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. Specifically in cortical interneurons, we have recently shown a cell-autonomous and stage-specific requirement for Rac1 activity within proliferating interneuron precursors. Conditional ablation of Rac1 in the medial ganglionic eminence leads to a 50% reduction of GABAergic interneurons in the postnatal cortex. Here we examine the additional role of Rac3 by analyzing Rac1/Rac3 double-mutant mice. We show that in the absence of both Rac proteins, the embryonic migration of medial ganglionic eminence-derived interneurons is further impaired. Postnatally, double-mutant mice display a dramatic loss of cortical interneurons. In addition, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with the length of their leading processes significantly reduced and a clear multipolar morphology. We propose that in the absence of Rac1/Rac3, cortical interneurons fail to migrate tangentially towards the pallium due to defects in actin and microtubule cytoskeletal dynamics.
    Cerebral Cortex 03/2014; 25(9). DOI:10.1093/cercor/bhu037 · 8.67 Impact Factor
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    • "In the cases where direct transcriptional regulation has been demonstrated, the lines are shown in bold ; otherwise the relationship is depicted with a dotted line . References: (Azim et al. 2009 ; Balamotis et al. 2012 ; Batista-Brito et al. 2009 ; Cobos et al. 2005a , b ; Cobos et al. 2007 ; Colasante et al. 2008 ; Colasante et al. 2009 ; Denaxa et al. 2012 ; Du et al. 2008 ; Long et al. 2009 ; McKinsey et al. 2013 ; Nobrega-Pereira et al. 2008 ; Tang et al. 2012 ; van den Berghe et al. 2013 ; Wang et al. 2010 ; Zhao et al. 2008 ) "
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    ABSTRACT: Inhibitory GABAergic interneurons within the cerebral cortex are critical for fi ne-tuning the activity of cortical circuits and thus are thought to be involved in generating the distinct oscillatory patterns that underlie higher brain functions such as consciousness and memory. Understanding how cortical interneurons are speci-fi ed during development is important not just from the standpoint of basic research but also is likely to provide key insights into how cognitive disorders emerge. Although interneurons only consist of around 20 % of the neurons within the neo-cortex, they are extremely diverse with regard to their morphologies, molecular expression profi les, intrinsic electrophysiological properties, and synaptic connec-tions. In rodents, most neocortical interneurons originate during embryogenesis from ventrally located structures, primarily the ganglionic eminences, and therefore must migrate over long distances following discrete pathways to reach the appropriate cortical areas. Thus, proper coordination of the distinct migration programs followed by pyramidal cells and interneuron precursors during development is crucial for the assembly of functional microcircuits within the cerebral cortex. Here, we review and discuss emerging views of how cortical GABAergic interneuron specifi cation, migra-tion, and integration occur from embryonic to early postnatal stages.
    Cortical Development: Neural Diversity and Neocortical Organization, Edited by R. Kageyama and T. Yamamori, 10/2013: chapter 5: pages 89-126; Springer.
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