Olig1 Function Is Required to Repress Dlx1/2 and Interneuron Production in Mammalian Brain

Abstract

Summary Abnormal GABAergic interneuron density, and imbalance of excitatory versus inhibitory tone, is thought to result in epilepsy, neurodevelopmental disorders and psychiatric disease. Recent studies indicate that interneuron cortical density is determined primarily by the size of the precursor pool in the embryonic telencephalon. However, factors essential to regulate interneuron allocation from telencephalic multipotent precursors are poorly understood. Here we report that Olig1 represses production of GABAergic interneurons throughout the mouse brain. Olig1 deletion in mutant mice results in ectopic expression and upregulation of Dlx1/2 genes in the ventral medial ganglionic eminences and adjacent regions of the septum resulting in a ~30% increase in adult cortical interneuron numbers. We show that Olig1 directly represses the Dlx1/2 I12b intergenic enhancer and that Dlx1/2 functions genetically downstream of Olig1. These findings establish Olig1 as an essential repressor of Dlx1/2 and interneuron production in developing mammalian brain.

OTX2 Transcription Factor Controls Regional Patterning within the Medial Ganglionic Eminence and Regional Identity of the Septum

“…Otx2 cKOs overexpress anti-neurogenic TFs ( Hes1 , Id4 ; Table S1; Figure 5) that inhibit neurogenic TFs such as Ascl1 ( Mash1 ) (Casarosa et al, 1999; Yun et al, 2002). Furthermore, Otx2 promotes oligodendrogenesis through positive regulation of Olig1 and Olig2 (Figure 4)(Petryniak et al, 2007; Silbereis et al, 2014). These mechanisms for neurogenesis and oligodendrogenesis appear to be mediated by direct binding of OTX2 at genomic loci of key regulatory TFs (Figure 2).…”

NPAS1 Represses the Generation of Specific Subtypes of Cortical Interneurons

“…A recent study demonstrates that Olig1 inhibits the generation of GABAergic interneurons produced in the MGE by repression of Dlx expression through the Dlx1/2 I12b intergenic enhancer (Silbereis et al, 2014). Likewise, NPAS1 inhibits the generation of cortical interneurons by repression of Arx expression through the subpallial Arx enhancer, which mediates CGE progenitor cell proliferation (Figure 7) (Colasante et al, 2008).…”

“…Some TFs regulate the development of either CGE or MGE derived neurons. For instance, Lhx6 , Nkx2-1 , Olig1 and Sox6 regulate for the specification and differentiation of MGE derived interneurons (Azim et al, 2009; Batista-Brito et al, 2009; Liodis et al, 2007; Silbereis et al, 2014; Sussel et al, 1999; Zhao et al, 2008). Other TF’s, such as the Arx and Dlx genes, control development of both CGE and MGE derived interneurons (Cobos et al, 2005; Colasante et al, 2008; Marsh et al, 2009).…”

From trans to cis: transcriptional regulatory networks in neocortical development

“…Interestingly, DLX1 and DLX2, TFs necessary for interneuron fate specification, and OLIG1 and OLIG2 control neuronal versus oligodendroglial cell fate acquisition in the developing ventral forebrain [51]. DLX1/2 promote neurogenesis at the expense of the oligodendrocyte lineage through repression of Olig2 expression [51, 52]. By contrast, OLIG1 directly binds to the Dlx1/2 I12b intergenic enhancer to repress Dlx1/2 expression, leading to the acquisition of an oligodendrocyte fate [52].…”

“…DLX1/2 promote neurogenesis at the expense of the oligodendrocyte lineage through repression of Olig2 expression [51, 52]. By contrast, OLIG1 directly binds to the Dlx1/2 I12b intergenic enhancer to repress Dlx1/2 expression, leading to the acquisition of an oligodendrocyte fate [52]. …”