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Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence.

ABSTRACT: The Gsx2 homeodomain transcription factor promotes neural progenitor identity in the lateral ganglionic eminence (LGE), despite upregulating the neurogenic factor Ascl1. How this balance in maturation is maintained is unclear. Here, we show that Gsx2 and Ascl1 are co-expressed in subapical progenitors that have unique transcriptional signatures in LGE ventricular zone (VZ) cells. Moreover, whereas Ascl1 misexpression promotes neurogenesis in dorsal telencephalic progenitors, the co-expression of Gsx2 with Ascl1 inhibits neurogenesis. Using luciferase assays, we found that Gsx2 reduces the ability of Ascl1 to activate gene expression in a dose-dependent and DNA binding-independent manner. Furthermore, Gsx2 physically interacts with the basic helix-loop-helix (bHLH) domain of Ascl1, and DNA-binding assays demonstrated that this interaction interferes with the ability of Ascl1 to bind DNA. Finally, we modified a proximity ligation assay for tissue sections and found that Ascl1-Gsx2 interactions are enriched within LGE VZ progenitors, whereas Ascl1-Tcf3 (E-protein) interactions predominate in the subventricular zone. Thus, Gsx2 contributes to the balance between progenitor maintenance and neurogenesis by physically interacting with Ascl1, interfering with its DNA binding and limiting neurogenesis within LGE progenitors.

SUBMITTER: Roychoudhury K

PROVIDER: S-EPMC7157596 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence

Project description:These findings suggest that physical interactions between Gsx2 and Ascl1 limit Ascl1:Ascl1 and Ascl1:Tcf3 interactions, and thereby inhibit Ascl1-dependennt neurogenesis and allow for progenitor expansion within the LGE.

2020-03-11 | GSE142768 | GEO

Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence

Project description:Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence

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The homeobox gene Gsx2 controls the timing of oligodendroglial fate specification in mouse lateral ganglionic eminence progenitors.

Project description:The homeobox gene Gsx2 has previously been shown to be required for the specification of distinct neuronal subtypes derived from lateral ganglionic eminence (LGE) progenitors at specific embryonic time points. However, its role in the subsequent generation of oligodendrocytes from these progenitors remains unclear. We have utilized conditional gain-of-function and loss-of-function approaches in order to elucidate the role of Gsx2 in the switch between neurogenesis and oligodendrogenesis within the embryonic ventral telencephalon. In the absence of Gsx2 expression, an increase in oligodendrocyte precursor cells (OPCs) with a concomitant decrease in neurogenesis is observed in the subventricular zone of the LGE at mid-stages of embryogenesis (i.e. E12.5-15.5), which subsequently leads to an increased number of Gsx2-derived OPCs within the adjacent mantle regions of the cortex before birth at E18.5. Moreover, using Olig2(cre) to conditionally inactivate Gsx2 throughout the ventral telencephalon with the exception of the dorsal (d)LGE, we found that the increase in cortical OPCs in Gsx2 germline mutants are derived from dLGE progenitors. We also show that Ascl1 is required for the expansion of these dLGE-derived OPCs in the cortex of Gsx2 mutants. Complementing these results, gain-of-function experiments in which Gsx2 was expressed throughout most of the late-stage embryonic telencephalon (i.e. E15.5-18.5) result in a significant decrease in the number of cortical OPCs. These results support the notion that high levels of Gsx2 suppress OPC specification in dLGE progenitors and that its downregulation is required for the transition from neurogenesis to oligodendrogenesis.

| S-EPMC3653554 | biostudies-literature

Transcriptomic analysis from lateral ganglionic eminence (LGE) of wild type and Gsx2 germline knock-out mice.

Project description:RNA-seq analysis was used to identify genes that are differentially expressed between wild type and Gsx2 null mouse LGEs.

2020-12-04 | GSE162590 | GEO

Characterization of Glcci1 expression in a subpopulation of lateral ganglionic eminence progenitors in the mouse telencephalon.

Project description:BACKGROUND:The lateral ganglionic eminence (LGE) in the ventral telencephalon is a diverse progenitor domain subdivided by distinct gene expression into a dorsal region (dLGE) that gives rise to olfactory bulb and amygdalar interneurons and a ventral region (vLGE) that gives rise to striatal projection neurons. The homeobox gene, Gsx2, is an enriched marker of the LGE and is expressed in a high dorsal to low ventral gradient in the ventricular zone (VZ) as development proceeds. Aside from Gsx2, markers restricted to the VZ in the dLGE and/or vLGE remain largely unknown. RESULTS:Here, we show that the gene and protein expression of Glucocorticoid-induced transcript 1 (Glcci1) has a similar dorsal to ventral gradient of expression in the VZ as Gsx2. We found that Glcci1 gene and protein expression are reduced in Gsx2 mutants, and are increased in the cortex after early and late Gsx2 misexpression. Moreover, Glcci1 expressing cells are restricted to a subpopulation of Gsx2 positive cells on the basal side of the VZ and co-express Ascl1, but not the subventricular zone dLGE marker, Sp8. CONCLUSIONS:These findings suggest that Glcci1 is a new marker of a subpopulation of LGE VZ progenitor cells in the Gsx2 lineage. Developmental Dynamics 247:222-228, 2018. © 2017 Wiley Periodicals, Inc.

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Bulk RNA-seq of the human fetal neocortex, lateral ganglionic eminence and medial ganglionic eminence at 7, 9, 11 and 20 post-conceptional weeks

Project description:Deep transcriptional profiling of the human neocortex, lateral ganglionic eminence (LGE) and medial ganglionic eminences (MGE), from 7 to 20 post-conceptional weeks (pcw), for de novo lincRNAs discovery and to establish a unique coding and non-coding gene signature for the three different regions.

2021-05-13 | E-MTAB-8893 | biostudies-arrayexpress

Gsx transcription factors control neuronal versus glial specification in ventricular zone progenitors of the mouse lateral ganglionic eminence.

Project description:The homeobox gene Gsx2 has previously been shown to inhibit oligodendroglial specification in dorsal lateral ganglionic eminence (dLGE) progenitors of the ventral telencephalon. The precocious specification of oligodendrocyte progenitor cells (OPCs) observed in Gsx2 mutants, however, is transient and begins to normalize by late stages of embryogenesis. Interestingly, this normalization correlates with the expansion of Gsx1, a close homolog of Gsx2, in a subset of progenitors in the Gsx2 mutant LGE. Here, we interrogated the mechanisms underlying oligodendroglial specification in Gsx2 mutants in relation to Gsx1. We found that Gsx1/2 double mutant embryos exhibit a more robust expansion of Olig2+ cells (i.e. OPCs) in the subventricular zone (SVZ) of the dLGE than Gsx2 mutants. Moreover, misexpression of Gsx1 throughout telencephalic VZ progenitors from E15 and onward resulted in a significant reduction of cortical OPCs. These results demonstrate redundant roles of Gsx1 and Gsx2 in suppressing early OPC specification in LGE VZ progenitors. However, Gsx1/2 mutants did not show a significant increase in adjacent cortical OPCs at later stages compared to Gsx2 mutants. This is likely due to reduced proliferation of OPCs within the SVZ of the Gsx1/2 double mutant LGE, suggesting a novel role for Gsx1 in expansion of migrating OPCs in the ventral telencephalon. We further investigated the glial specification mechanisms downstream of Gsx2 by generating Olig2/Gsx2 double mutants. Consistent with the known essential role for Olig2 in OPC specification, ectopic production of cortical OPCs observed in Gsx2 mutants disappeared in Olig2/Gsx2 double mutants. These mutants, however, maintained the expanded expression of gliogenic markers Zbtb20 and Bcan in the VZ of the LGE similarly to Gsx2 single mutants, suggesting that Gsx2 suppresses gliogenesis via Olig2-dependent and -independent mechanisms.

| S-EPMC6158017 | biostudies-literature

Sp9 Regulates Medial Ganglionic Eminence-Derived Cortical Interneuron Development.

Project description:Immature neurons generated by the subpallial MGE tangentially migrate to the cortex where they become parvalbumin-expressing (PV+) and somatostatin (SST+) interneurons. Here, we show that the Sp9 transcription factor controls the development of MGE-derived cortical interneurons. SP9 is expressed in the MGE subventricular zone and in MGE-derived migrating interneurons. Sp9 null and conditional mutant mice have approximately 50% reduction of MGE-derived cortical interneurons, an ectopic aggregation of MGE-derived neurons in the embryonic ventral telencephalon, and an increased ratio of SST+/PV+ cortical interneurons. RNA-Seq and SP9 ChIP-Seq reveal that SP9 regulates MGE-derived cortical interneuron development through controlling the expression of key transcription factors Arx, Lhx6, Lhx8, Nkx2-1, and Zeb2 involved in interneuron development, as well as genes implicated in regulating interneuron migration Ackr3, Epha3, and St18. Thus, Sp9 has a central transcriptional role in MGE-derived cortical interneuron development.

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Interneuron Origins in the Embryonic Porcine Medial Ganglionic Eminence.

Project description:Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6, and Dlx2 expression, in vitro differentiation into neurons expressing GABA, and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies.SIGNIFICANCE STATEMENT Here we demonstrate that porcine medial ganglionic eminence, like rodents, exhibit a distinct transcriptional and interneuron-specific antibody profile, in vitro migratory capacity and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic interneuron origins in the pig; and because a rich neurodevelopmental literature on embryonic mouse medial ganglionic eminence exists (with some additional characterizations in other species, e.g., monkey and human), our work allows direct neurodevelopmental comparisons with this literature.

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Understanding and modeling regional specification of the human ganglionic eminence.

Project description:Inhibitory neurons originating from the ventral forebrain are associated with several neurological conditions. Distinct ventral forebrain subpopulations are generated from topographically defined zones; lateral-, medial- and caudal ganglionic eminences (LGE, MGE and CGE), yet key specification factors often span across developing zones contributing to difficulty in defining unique LGE, MGE or CGE profiles. Here we use human pluripotent stem cell (hPSC) reporter lines (NKX2.1-GFP and MEIS2-mCherry) and manipulation of morphogen gradients to gain greater insight into regional specification of these distinct zones. We identified Sonic hedgehog (SHH)-WNT crosstalk in regulating LGE and MGE fate and uncovered a role for retinoic acid signaling in CGE development. Unraveling the influence of these signaling pathways permitted development of fully defined protocols that favored generation of the three GE domains. These findings provide insight into the context-dependent role of morphogens in human GE specification and are of value for in vitro disease modeling and advancement of new therapies.

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