The LIM-Homeobox Gene<i>Islet-1</i>Is Required for the Development of Restricted Forebrain Cholinergic Neurons

Elshatory, Yasser; Gan, Lin

doi:10.1523/jneurosci.5730-07.2008

Cited by 75 publications

(82 citation statements)

References 33 publications

(41 reference statements)

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“…Isl1 is expressed in cholinergic SINs in rodents (Wang and Liu, 2001) and is required for the differentiation of subsets of FCNs in mice (Elshatory and Gan, 2008). Consistent with these reports, in Lhx7 +/nlacZ animals Isl1 was detected in 61.8±2.0% of LacZ + striatal cells (Fig.…”

Section: A) -Galsupporting

confidence: 85%

LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons

Fragkouli¹,

Wijk²,

Lopes³

et al. 2009

Development

115

111

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Coordination of voluntary motor activity depends on the generation of the appropriate neuronal subtypes in the basal ganglia and their integration into functional neuronal circuits. The largest nucleus of the basal ganglia, the striatum, contains two classes of neurons: the principal population of medium-sized dense spiny neurons (MSNs; 97-98% of all striatal neurons in rodents), which project to the globus pallidus and the substantia nigra, and the locally projecting striatal interneurons (SINs; 2-3% in rodents). SINs are further subdivided into two non-overlapping groups: those producing acetylcholine (cholinergic) and those producing -amino butyric acid (GABAergic). Despite the pivotal role of SINs in integrating the output of striatal circuits and the function of neuronal networks in the ventral forebrain, the lineage relationship of SIN subtypes and the molecular mechanisms that control their differentiation are currently unclear. Using genetic fate mapping, we demonstrate here that the majority of cholinergic and GABAergic SINs are derived from common precursors generated in the medial ganglionic eminence during embryogenesis. These precursors express the LIM homeodomain protein Lhx6 and have characteristics of proto-GABAergic neurons. By combining gene expression analysis with loss-of-function and misexpression experiments, we provide evidence that the differentiation of the common precursor into mature SIN subtypes is regulated by the combinatorial activity of the LIM homeodomain proteins Lhx6, Lhx7 (Lhx8) and Isl1. These studies suggest that a LIM homeodomain transcriptional code confers cell-fate specification and neurotransmitter identity in neuronal subpopulations of the ventral forebrain.

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Section: A) -Galsupporting

confidence: 85%

LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons

Fragkouli¹,

Wijk²,

Lopes³

et al. 2009

Development

115

111

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“…2B, arrowhead). The forebrain of ChAT::Cre;Lhx7 fl/LacZ animals was also analyzed for expression of Isl1, a gene expressed in mature CSIs and required for their specification (8,11). Consistent with the loss of CSIs, the number of cells expressing Isl1 was severely reduced (compare Fig.…”

Section: Resultsmentioning

confidence: 95%

“…In contrast, Lhx6 is undetectable in CSIs, which invariably coexpress Isl1 and Lhx7. Genetic studies have established the requirement of Lhx7 and Isl1 for the specification of forebrain cholinergic neurons (11)(12)(13)(14), but the potential role of these factors in maintaining the identity of CSIs following their specification and differentiation is currently unknown.…”

mentioning

confidence: 99%

Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum

Lopes

Wijk

Neves

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The generation and maintenance of a plethora of neuronal subtypes is essential for normal brain function. Nevertheless, little is known about the molecular mechanisms that maintain the defining characteristics of neurons following their initial postmitotic specification. Using conditional gene ablation in mice, we demonstrate here that the homeodomain protein LIM homeobox (Lhx)7 is essential for maintaining the morphological and molecular characteristics of cholinergic interneurons of the striatum. Lhx7-depleted cholinergic interneurons extinguish expression of several subtype-specific markers, including choline acetyl transferase and Isl1, and are respecified into Lhx6-expressing mature GABAergic interneurons. Additional expression studies support a model where Lhx7 controls the choice between cholinergic or GABAergic identity by gating a cross inhibitory regulation between Isl1 and Lhx6. By demonstrating that the switch between alternative striatal interneuron fates depends on persistent activity of a single transcription factor, we provide evidence that the intrinsic plasticity of mammalian forebrain neuronal subtypes is maintained after the initial specification and lineage commitment and possibly throughout life.neuronal subtype specification | medial ganglionic eminence-derived interneurons T he information-processing ability of the nervous system depends on the formation of functional neuronal circuits composed of a highly heterogeneous population of neurons. Recent progress has identified molecular cascades that control the generation of distinct neuronal subtypes during development (1-3) but the mechanisms that maintain the identity of neurons following lineage commitment and differentiation are currently unclear. Identifying such mechanisms is critical for understanding phenotypic plasticity in the nervous system and, ultimately, influencing its ability to adjust during normal development, disease, or injury.The striatum is a subcortical structure that integrates multiple inputs from the cortex, thalamus, and midbrain and relays information to the output domains of the basal ganglia via its principal population of projection neurons (4, 5). Balanced striatal output, which is critical for motor and cognitive activity, depends on local circuits controlled by distinct subpopulations of GABAergic and cholinergic interneurons (5). Both GABAergic and cholinergic striatal interneurons (GSIs and CSIs, respectively) are derived from Nkx2.1-expressing progenitors of the medial ganglionic eminence (MGE) (6, 7), which, upon exit from the cell cycle, express the LIM homeodomain (LIM HD) transcription factors LIM homeobox 6 (Lhx6) and LIM homeobox 7 (Lhx7) (8). A subset of these precursors maintains expression of Lhx6 and differentiate into mature GABAergic interneurons expressing the neuropeptide somatostatin (Sst) or the calcium-binding protein parvalbumin (Pv) (9, 10). The remaining precursors induce expression of the LIM HD protein Isl1, down-regulate Lhx6, and differentiate into CSIs (8). In adult animals, all ...

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“…The mechanisms of the Meis2-and Islet-1-positive corridor expansion, including whether it is a real expansion or dispersion brought about by the loss of Nkx2-1-positive globus pallidus, and the significance of the corridor abnormality in TCA projection require additional studies. No reduction of corridor was reported in Islet1 knock-out mutants (Elshatory and Gan, 2008), but the effects of Islet1 overexpression RNA in situ hybridization of Nkx2.1 for the proliferating field of the MGE and globus pallidus at E13.5 (E, F), of Islet1 for corridor in sections adjacent to E and F (E,F), and of Nkx2.1 (G, H) and Meis2 (G, H) for the ventral telencephalon in adjacent sections at E15.5. I, J, Anti-Pax6 (green) and Tuj1 (red) staining in the E15.5 subpallium.…”

Section: Discussionmentioning

confidence: 94%

MicroRNA-9 Regulates Neurogenesis in Mouse Telencephalon by Targeting Multiple Transcription Factors

Shibata

Nakao²,

Kanazawa³

et al. 2011

J. Neurosci.

307

299

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microRNA-9-2 and microRNA-9-3 double-mutant mice demonstrate that microRNA-9 (miR-9) controls neural progenitor proliferation and differentiation in the developing telencephalon by regulating the expression of multiple transcription factors. As suggested by our previous study, the Foxg1 expression was elevated, and the production of Cajal-Retzius cells and early-born neurons was suppressed in the miR-9-2/3 double-mutant pallium. At embryonic day 16.5 (E16.5), however, the Foxg1 expression was no longer elevated. The expression of an AU-rich RNA-binding protein Elavl2 increased at E16.5, Elav2 associated with Foxg1 3Ј untranslated region (UTR), and it countered the Foxg1 suppression by miR-9. Later, progenitor proliferation was reduced in the miR-9-2/3 double-mutant pallium with the decrease in Nr2e1 and Pax6 expression and the increase in Meis2 expression. The analyses suggest that microRNA-9 indirectly inhibits Pax6 expression by suppressing Meis2 expression. In contrast, together with Elavl1 and Msi1, microRNA-9 targets Nr2e1 mRNA 3Ј UTR to enhance the expression. Concomitantly, cortical layers were reduced, each cortical projection was malformed, and the tangential migration of interneurons into the pallium was impaired in the miR-9-2/3 double mutants. miR-9 also targets Gsh2 3Ј UTR, and Gsh2, as well as Foxg1, expression was elevated in the miR-9-2/3 double-mutant subpallium. The subpallium progenitor proliferation was enhanced, and the development of basal ganglia including striatum and globus pallidus was suppressed. Pallial/subpallial boundary shifted dorsally, and the ventral pallium was lost. Corridor was malformed, and thalamocortical and corticofugal axons were misrouted in the miR-9-2/3 double mutants.

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The LIM-Homeobox GeneIslet-1Is Required for the Development of Restricted Forebrain Cholinergic Neurons

Cited by 75 publications

References 33 publications

LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons

LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons

Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum

MicroRNA-9 Regulates Neurogenesis in Mouse Telencephalon by Targeting Multiple Transcription Factors

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