Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

Lindtner, Susan; Catta-Preta, Rinaldo; Tian, Hua; Su-Feher, Linda; Price, James D.; Dickel, Diane E.; Greiner, Vanille J.; Silberberg, Shanni N.; McKinsey, Gabriel L.; McManus, Michael T.; Pennacchio, L; Visel, Axel; Nord, Alexander; Rubenstein, John L.R.

doi:10.2139/ssrn.3372973

Cited by 20 publications

(38 citation statements)

References 65 publications

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“…Our analyses indicate that the ventral Gsx2 à Ascl1 à Dlx1/2 transcriptional pathway is enriched in ShhPCs. This is consistent with some ShhPCs being committed to the OB-IN lineage (Zhang et al, 2020), as this pathway is important for generating OB-INs (Guo et al, 2019;Lindtner et al, 2019). In addition to its roles in neurogenesis, Ascl1 genetically interacts with Olig2 and is critical for normal production of oligodendrocytes in the spinal cord and ventral forebrain (Nakatani et al, 2013;Parras et al, 2007;Sugimori et al, 2007).…”

Section: Cross-repressive Gene Regulatory Network For Neurogenesis Asupporting

confidence: 69%

“…In the developing chick forebrain, Dlx1/2 are necessary and sufficient to repress oligodendrocyte specification via transcriptional inhibition of Olig2 (Jiang et al, 2020). Dlx1/2 also repress Gsx2 (Guo et al, 2019) and activate Sp8 and Sp9 expression (Lindtner et al, 2019), which are essential for OB-IN maturation (Guo et al, 2019;Li et al, 2018). Pax6 is also required to generate a subset of OB-INs (Kohwi et al, 2005), and we found that Pax6 levels are initially decreased in ShhPCs before increasing again specifically in the OB-IN lineage.…”

Section: Cross-repressive Gene Regulatory Network For Neurogenesis Amentioning

confidence: 54%

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Unraveling the transcriptional networks that drive oligodendrocyte fate specification in Sonic hedgehog-responsive neocortical progenitors

Winkler

Tran

Milan

et al. 2020

Preprint

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In the developing nervous system, progenitors first generate neurons before making astrocytes and oligodendrocytes. We previously showed that increased Sonic hedgehog (Shh) signaling in dorsal forebrain progenitors is important for their production of oligodendrocytes as neurogenesis winds down. Here, we analyzed single-cell RNA sequencing datasets to better understand how Shh controls this neuron-to-oligodendrocyte switch in the neocortex. We first identified Shh-responding progenitors using a dataset in which Shh was overexpressed in the mouse dorsal forebrain. Pseudotime trajectory inferences revealed a subpopulation committed to the oligodendrocyte precursor cell (OPC) lineage. Genes upregulated along this lineage defined a pre-OPC state, as cells transitioned from progenitors to OPCs. Using several datasets from wild-type mouse and human embryos at different ages, we confirmed a pre-OPC state preceding OPC emergence during normal development. Finally, we show that pre-OPCs are enriched for a gene regulatory network involving the transcription factor Ascl1. Genetic lineage-tracing demonstrated Ascl1-positive dorsal progenitors primarily make oligodendrocytes. We propose a model in which Shh shifts the balance between opposing transcriptional networks toward an Ascl1 lineage, thereby facilitating the switch between neurogenesis and oligodendrogenesis.

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Section: Cross-repressive Gene Regulatory Network For Neurogenesis Asupporting

confidence: 69%

Section: Cross-repressive Gene Regulatory Network For Neurogenesis Amentioning

confidence: 54%

Unraveling the transcriptional networks that drive oligodendrocyte fate specification in Sonic hedgehog-responsive neocortical progenitors

Winkler

Tran

Milan

et al. 2020

Preprint

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“…It has been proposed that interactions between Prdm family proteins and bHLH transcription factors is a conserved mechanism for the regulation of gene expression during neural development (Hohenauer and Moore, 2012;Ross et al, 2012). Such transcription factor complexes may function in the proliferative zones where they are expressed in order to direct differentiation/lineage progression programs towards region-specific neuronal subtype specification (Lindtner et al, 2019). Our genomic analysis of PRDM16 binding in MGE progenitors sheds light on the lineage-specific transcriptional programs regulated by PRDM16 and suggests that specialized PRDM16-associated protein complexes may orchestrate these programs in different progenitor types.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production

García

Baizabal

Tran

et al. 2019

Preprint

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The mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from progenitors located in the dorsal telencephalon, while inhibitory interneurons are generated by ventral telencephalic progenitors. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear if PRDM16 functions plays a role in neurogenesis in both dorsal and ventral progenitor lineages, and if so, whether it does so by regulating common or unique networks of genes. Here, we show that Prdm16 expression in MGE progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of pallial GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. Our results highlight the importance of PRDM16 for the development of both excitatory and inhibitory cortical circuits. We demonstrate the existence of convergent developmental gene expression programs regulated by PRDM16, which utilize both common and region-specific sets of genes in the cortex and the MGE to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.

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“…Like Ascl1, the Dlx genes require Gsx2 for their correct expression in LGE progenitors (Toresson et al, 2000, Corbin et al, 2000, Yun et al, 2001, Wang et al, 2013). Both Ascl1 and Dlx factors have been shown to promote the differentiation of GABAergic neuronal phenotypes typical of the LGE (Yun et al, 2002, Long et al, 2009a, 2009b, Pla et al, 2018, Lindtner et al, 2019). Furthermore, loss of Gsx2 leads to an upregulation of the oligodendrocyte precursor cell marker Pdgfr α (Corbin et al, 2003) and concomitant precocious oligodendrocyte differentiation (Chapman et al, 2013, 2018).…”

Section: Discussionmentioning

confidence: 99%

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

Roychoudhury

Salomone

Qin

et al. 2019

Preprint

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The Gsx2 homeodomain transcription factor is required to maintain neural progenitor identity in the lateral ganglionic eminence (LGE) within the developing ventral telencephalon, despite its role in upregulating the neurogenic factor Ascl1. How Gsx2 maintains cells as progenitors in the presence of a pro-differentiation factor is unclear. Here, we show that Gsx2 and Ascl1 are coexpressed in dividing subapical progenitors within the LGE ventricular zone (VZ). Moreover, we show that while Ascl1 misexpression promotes neurogenesis in dorsal telencephalic progenitors that do not express Gsx2, co-expression of Gsx2 with Ascl1 inhibits neurogenesis in these cells.To investigate the mechanisms underlying this inhibition, we used a cell-based luciferase assay to show that Gsx2 reduced the ability of Ascl1 to activate target gene expression in a dosedependent and DNA binding-independent manner. Yeast 2-hybrid and co-immunoprecipitation assays revealed that 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 form homo-or heterodimers with E-proteins such as Tcf3 on DNA. To further assess for in vivo molecular interactions between these transcription factors within the telencephalon, we modified a proximity ligation assay for embryonic tissue sections and found that Ascl1:Gsx2 interactions are enriched within VZ progenitors, whereas Ascl1:Tcf3 interactions predominate in basal progenitors. Altogether, 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. This work was supported by NIH R01 NS044080 to K.C. and B.G. and NS069893 to M.N. and K.C. . et al. (2008). Variation in 29 homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell. 1266-1276. 133,

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Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

Cited by 20 publications

References 65 publications

Unraveling the transcriptional networks that drive oligodendrocyte fate specification in Sonic hedgehog-responsive neocortical progenitors

Unraveling the transcriptional networks that drive oligodendrocyte fate specification in Sonic hedgehog-responsive neocortical progenitors

Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production

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

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