COUP-TFII controls amygdala patterning by regulating neuropilin expression

Abstract

SUMMARYThe development of the progenitor zones in the pallium, lateral ganglionic eminence (LGE) and medial ganglionic eminence (MGE) in the subpallium has been well studied; however, so far the role of the caudal ganglionic eminence (CGE), a posterior subpallial domain, in telencephalon patterning remains poorly understood. COUP-TFII, an orphan nuclear receptor, is preferentially expressed in the CGE. We generated COUP-TFII mouse mutants, using Rx-Cre (RxCre;COUP-TFII F/F ), to study its function in telencephalon development. In these mutants, we found severe defects in the formation of the amygdala complex, including the lateral (LA), basolateral (BLA) and basomedial (BMA) amygdala nuclei. Molecular analysis provided evidence that the migration of CGE-derived Pax6 + cells failed to settle into the BMA nucleus, owing to reduced expression of neuropilin 1 (Nrp1) and Nrp2, two semaphorin receptors that regulate neuronal cell migration and axon guidance. Our ChIP assays revealed that Nrp1 and Nrp2 genes are the direct targets of COUP-TFII in the telencephalon in vivo. Furthermore, our results showed that the coordinated development between the CGE originated subpallial population (Pax6 + cells) and pallial populations (Tbr1 + and Lhx2 + cells) was essential for patterning the amygdala assembly. Our study presented novel genetic evidence that the caudal ganglionic eminence, a distinct subpallial progenitor zone, contributes cells to the basal telencephalon, such as the BMA nucleus.

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

“…S10). However, it has been reported recently that Nrp1 expression is also directly regulated by COUP-TFII (23). We confirmed that Nrp1 has a similar function with that of Nrp2 in inhibiting the detachment of the POa-derived cells from the CMS and their accumulation in the amygdala (Fig.…”

“…The present study indicates that COUP-TFII caused and/or maintained the caudal migration of POa-derived cells. In support of this hypothesis, a recent study demonstrated hypoplasia or complete loss of the medial amygdala in COUP-TFII conditional knockout mice (23), suggesting that COUP-TFII expression is necessary for caudal migration of POa-derived GABAergic neurons in the formation of the medial amygdala. By contrast, cortical GABAergic neurons derived from the COUP-TFIIexpressing domain were reported to remain unaltered in COUP-TFII conditional knockout (RxCre;COUP-TF F/F ) mice (23).…”

“…In support of this hypothesis, a recent study demonstrated hypoplasia or complete loss of the medial amygdala in COUP-TFII conditional knockout mice (23), suggesting that COUP-TFII expression is necessary for caudal migration of POa-derived GABAergic neurons in the formation of the medial amygdala. By contrast, cortical GABAergic neurons derived from the COUP-TFIIexpressing domain were reported to remain unaltered in COUP-TFII conditional knockout (RxCre;COUP-TF F/F ) mice (23). However, given the results that (i) COUP-TFII expression in this conditional knockout mouse was weakly observed at E12.5 in the ventral telencephalon (23) and (ii) COUP-TFII expression was down-regulated in the POa-derived cortical GABAergic neurons, weak expression of COUP-TFII in POa-derived cells at early stages might be sufficient for their ultimate distribution in the cortex.…”

“…It is well established that in lymphatic vessels, COUP-TFII binds the promoter region of Nrp2 via SP1 and induces Nrp2 expression (22). The same regulation process of the Nrp2 expression by COUP-TFII has recently been reported in the developing murine forebrain at E12.5 (23). To investigate whether Nrp2 expression is also regulated by COUP-TFII in the CMS, realtime PCR on fluorescence-activated cell sorted (FACS) POaderived cells was performed.…”

“…By contrast, cortical GABAergic neurons derived from the COUP-TFIIexpressing domain were reported to remain unaltered in COUP-TFII conditional knockout (RxCre;COUP-TF F/F ) mice (23). However, given the results that (i) COUP-TFII expression in this conditional knockout mouse was weakly observed at E12.5 in the ventral telencephalon (23) and (ii) COUP-TFII expression was down-regulated in the POa-derived cortical GABAergic neurons, weak expression of COUP-TFII in POa-derived cells at early stages might be sufficient for their ultimate distribution in the cortex. Further studies are required to draw a final conclusion about the requirement of COUP-TFII for the migration of cortical interneurons.…”