Lhx6 Directly Regulates Arx and CXCR7 to Determine Cortical Interneuron Fate and Laminar Position

Abstract

SUMMARY Cortical GABAergic interneurons have essential roles for information processing and their dysfunction is implicated in neuropsychiatric disorders. Transcriptional codes are elucidating mechanisms of interneuron specification in the MGE (a subcortical progenitor zone), which regulate their migration, integration, and function within cortical circuitry. Lhx6, a LIM-homeodomain transcription factor, is essential for specification of MGE-derived somatostatin and parvalbumin interneurons. Here, we demonstrate that some Lhx6−/− MGE cells acquire a CGE-like fate. Using an in vivo MGE complementation/transplantation assay, we show that Lhx6-regulated genes Arx and CXCR7 rescue divergent aspects of Lhx6−/− cell-fate and laminar mutant phenotypes and provide insight into a neonatal role for CXCR7 in MGE-derived interneuron lamination. Finally, Lhx6 directly binds in vivo to an Arx enhancer and to an intronic CXCR7 enhancer that remains active in mature interneurons. These data define the molecular identity of Lhx6 mutants and introduce technologies to test mechanisms in GABAergic interneuron differentiation.

Coup-TF1 and Coup-TF2 control subtype and laminar identity of MGE-derived neocortical interneurons

“…S3D,E). Lhx6 and Sox6 expression, TFs that promote SST + fate (Azim et al, 2009;BatistaBrito et al, 2009;Zhao et al, 2008;Vogt et al, 2014), was decreased in tangentially migrating interneurons (Fig. S3F,G), and in the SVZ and MZ of the caudal MGE (Fig.…”

Interneuron Transplantation as a Treatment for Epilepsy

“…The MGE is the primary source of inhibitory neurons expressing parvalbumin (PV), somatostatin (SST), or neuronal nitric oxide synthase (nNOS), and MGE identity is specified largely by expression of Nkx2-1, Lhx6, Sox6, and Satb1 transcription factors (Wichterle et al 2001;Xu et al 2004;Butt et al 2005;Alvarez-Dolado et al 2006;Flames et al 2007;Tricoire et al 2010Tricoire et al , 2011Vogt et al 2014). The CGE gives rise to inhibitory neurons expressing the serotonin receptor, 5HT3A, which includes vasoactive peptide (VIP)-, calretinin (CR)-, and reelin-positive interneurons that do not express SST (Lee et al 2010;Miyoshi et al 2010;Tricoire et al 2011).…”

Chemokine signaling in development and disease

“…These observations suggest that CXCR7 can act as an efficient chemokine sink because it can successfully compete with CXCR4 for access to the ligand, and a single receptor can undergo multiple rounds of ligand-induced internalization to target CXCL12 for degradation. G-protein-independent signaling through β-arrestins has also been demonstrated in several systems, including in interneurons, where CXCR7 elicits pERK signaling to modulate cell fate (Vogt et al, 2014;Wang et al, 2011).…”