The COUP-TFII/Neuropilin-2 is a molecular switch steering diencephalon-derived GABAergic neurons in the developing mouse brain

Abstract

The preoptic area (POa) of the rostral diencephalon supplies the neocortex and the amygdala with GABAergic neurons in the developing mouse brain. However, the molecular mechanisms that determine the pathway and destinations of POa-derived neurons have not yet been identified. Here we show that Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII)-induced expression of Neuropilin-2 (Nrp2) and its down-regulation control the destination of POa-derived GABAergic neurons. Initially, a majority of the POa-derived migrating neurons express COUP-TFII and form a caudal migratory stream toward the caudal subpallium. When a subpopulation of cells steers toward the neocortex, they exhibit decreased expression of COUP-TFII and Nrp2. The present findings show that suppression of COUP-TFII/Nrp2 changed the destination of the cells into the neocortex, whereas overexpression of COUP-TFII/Nrp2 caused cells to end up in the medial part of the amygdala. Taken together, these results reveal that COUP-TFII/Nrp2 is a molecular switch determining the pathway and destination of migrating GABAergic neurons born in the POa.

Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

“…CNVs of NR2F2 occur in individuals with ASD and ID, as well as heart defects (Nava et al, 2014). NR2F2 is highly expressed in the caudal ganglionic eminence and migrating interneurons (Kanatani et al, 2015), and is downregulated as interneurons enter the cerebral cortex. Therefore, abnormal NR2F2 expression may disrupt interneuron migration.…”

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

“…In green, the CGE-derived LMS and MMS described in this study, and the CMS described previously (Kanatani et al, 2008;Yozu et al, 2005). In red, the MGE-derived dorsal stream to the cortex (Ctx) reviewed by Guo and Anton (2014) and Marıń (2013), and in magenta, the POA-derived ventral stream to the amygdala (AM) and cortex described previously (Hirata et al, 2009;Kanatani et al, 2015;Puelles et al, 2015). In blue, the dLGEderived rostral stream migrating to the olfactory bulb (OB) and described by Batista-Brito et al (2008) and Waclaw et al (2006).…”

“…Interestingly, COUP-TFI controls the rate of CGE-migrating cells rostrally to the LGE and MGE, but not to the caudal pole. This is very different from COUP-TFII, which is crucial for driving CGE cells caudally (Kanatani et al, 2008(Kanatani et al, , 2015. Thus, whereas COUP-TFI restricts the number of CGE cells migrating rostrally, COUP-TFII promotes CGE cells to take caudal directions.…”

“…This is already substantiated by the CMS, which directs CGE cells to more caudal brain structures, such as the hippocampus (Chittajallu et al, 2013;Yozu et al, 2005). Here, we propose that the MMS populates the amygdala, as already suggested by short- term in vitro grafts (Vucurovic et al, 2010) and now supported by this study: (1) the majority of E14.5 CGE-grafted cells populate the amygdala in juvenile brains; (2) the massive cohort of GFP + cells migrating medially is abundant at E12/E13, a stage when CGEderived cortical INs normally represent only a small fraction (Lee et al, 2010;Miyoshi et al, 2010;Nery et al, 2002;Vucurovic et al, 2010); and (3) the MMS is highly represented by cells expressing COUP-TFII, which plays a relevant role in amygdala patterning (Tang et al, 2012) and which drives POA-derived cells to the medial amygdala (Kanatani et al, 2015).…”

“…However, CGE-derived INs are not only dispersed all over the cortex but are also found in various brain regions in the adult, including the hippocampus and amygdala (Chittajallu et al, 2013;Lee et al, 2010;Miyoshi et al, 2010;Nery et al, 2002;Vucurovic et al, 2010;Yozu et al, 2005); how they reach their final positions during development is still unclear (Tanaka and Nakajima, 2012). In addition, apart from COUP-TFII (Kanatani et al, 2008(Kanatani et al, , 2015, the molecular mechanisms controlling the tangential migration of CGE-derived cells remain to be elucidated.…”