Nuclear receptor COUP‐TFII‐expressing neocortical interneurons are derived from the medial and lateral/caudal ganglionic eminence and define specific subsets of mature interneurons

Abstract

Neocortical GABAergic interneurons in rodents originate from subpallial progenitor zones. The majority of mouse neocortical interneurons are derived from the medial and caudal ganglionic eminences (MGE and CGE, respectively) and the preoptic area (POA). It is controversial whether the lateral ganglionic eminence (LGE) also generates neocortical interneurons. Previously it was shown that the transcription factor COUP-TFII is expressed in the CGE; here we show that COUP-TFII is also expressed in the dorsal MGE, dorsal LGE (dMGE and dLGE, respectively), and POA. In the adult neocortex, COUP-TFII+/somatostatin (SOM)+ interneurons are mainly located in layer V. Using a genetic fate-mapping approach (Shh-Cre and Nkx2.1-Cre), we demonstrate that the POA and ventral MGE do not give rise to COUP-TFII+ neocortical interneurons, suggesting that the dMGE is the source of COUP-TFII+/SOM+ neocortical interneurons. We also observed a migratory stream of COUP-TFII+/Sp8+ cells emanating from the dLGE and CGE to the neocortex mainly through the subventricular zone at later embryonic stages. Slice culture experiments in which dLGE progenitors were labeled with BrdU provided additional evidence that the dLGE generates neocortical interneurons. While earlier-born dMGE-derived COUP-TFII+ interneurons occupy cortical layer V, later-born dLGE- and CGE-derived COUP-TFII+ ones preferentially occupy superficial cortical layers. A similar laminar distribution was observed following neonatal transplantation of embryonic day (E)14.5 dMGE and E15.5 dLGE. These results provide novel information about interneuron fate and position from spatially and temporally distinct origins in the ganglionic eminences.

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

“…1G,I,J; Fig. S12A), including in layer V, where most MGE-derived COUP-TF2 + cells are located (Cai et al, 2013). Thus, Coup-TF2-sensitized mutants had a transient decrement of Nkx2.1-Cre lineage cells migrating to the neocortex.…”

“…Multiple lines of evidence show that Coup-TF1/2 have key roles in promoting SST + interneuron development. Previously, layer V SST + CINs were shown to express COUP-TF2 (Cai et al, 2013). Here we demonstrate that Coup-TF2-sensitized mutants (in vivo genetics and MGE-transplant experiments) have a reduced neocortical SST + /PV + ratio ( Fig.…”

“…We focused on Coup-TF2 (Nr2f2) function (steroid/thyroid hormone receptor superfamily member) because it, and its paralogue Coup-TF1 (Nr2f1), are expressed in the MGE, and are largely confined to layer V SST + CINs (Cai et al, 2013;Lodato et al, 2011). Previous work on Coup-TF1 and Coup-TF2 in the embryonic basal ganglia focused on their function in the caudal ganglionic eminence (CGE) and amygdala (Lodato et al, 2011;Tang et al, 2012), although loss of Coup-TF1 decreased SST/PV balance (Lodato et al, 2011).…”

Molecular control of two novel migratory paths for CGE-derived interneurons in the developing mouse brain

“…3). COUP-TF nuclear receptors are preferentially restricted to the CGE from E13.5 and maintained in CGE-derived cortical INs (Cai et al, 2013;Kanatani et al, 2008;Lodato et al, 2011b;Tripodi et al, 2004). The transcription factor SP8 is expressed in CGE-derived cortical INs and in dorsal LGE (dLGE)-derived olfactory bulb INs (Ma et al, 2012), whereas PROX1 is highly expressed in CGE-derived cortical INs and in a subpopulation of POA-derived INs (Rubin and Kessaris, 2013;Miyoshi et al, 2015).…”

“…The orphan nuclear receptors COUP-TFI (also called Nr2f1) and COUP-TFII (Nr2f2) were the first transcriptional regulators found to be enriched in the CGE and required in the migration of GABAergic INs (Tripodi et al, 2004). Whereas COUP-TFII acts mainly in directing CGE-derived cells to the caudal migratory stream (CMS) (Cai et al, 2013;Kanatani et al, 2008;Yozu et al, 2005), COUP-TFI is required for the correct balance between MGE-and CGE-derived INs in the developing neocortex (Lodato et al, 2011b), but its role in migration is less known. 5HT3aR is expressed in migrating and mature CGE-and POA-derived cells (Lee et al, 2010;Vucurovic et al, 2010) and is cell-autonomously required for the migration and positioning of RLN + INs in the neocortex (Murthy et al, 2014).…”