Highlights d NR2F1-R112K mutation causes excitatory and inhibitory neuron imbalance d Activation of the Hedgehog pathway mainly accounts for the imbalance d Nr2f1 +/m mice display behavioral deficits of neurodevelopmental disorder, such as ASD d Ginkgolide A treatment partially alleviates behavioral deficits of Nr2f1 +/m mice

The paraventricular nucleus of hypothalamus plays important roles in the regulation of energy balance and fetal growth. However, the molecular mechanisms underlying its formation and function have not been clearly elucidated. Various mutations in the human COUP-TFII gene, which encodes a nuclear receptor, result in growth retardation, congenital diaphragmatic hernia and congenital heart defects. Here, we show that COUP-TFII gene is expressed in the developing hypothalamus in mouse. The ventral forebrain-specific RXCre/+; COUP-TFIIF/F mutant mice display growth retardation. The development of the paraventricular nucleus of hypothalamus is compromised in the COUP-TFII mutant mainly because of increased apoptosis and mis-migration of the Brn2+ neurons. Moreover, hypoplastic anterior pituitary with blood cell clusters and shrunken posterior pituitary lacking AVP/OT neuron innervations are observed in the mutant, indicating the failure of formation of the hypothalamic-pituitary axis. Mechanistic studies show that the expression of Bdnf and Nrp1 genes is reduced in the mutant embryo, and that Bdnf is a direct downstream target of the COUP-TFII protein. Thus, our findings provide a novel functional validation that COUP-TFII gene promotes the expression of Bdnf and Nrp1 genes to ensure the appropriate morphogenesis of the hypothalamic-pituitary axis, especially the paraventricular nucleus of hypothalamus, and to prevent growth retardation.

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Central nervous system including brain and retina is composed of appropriate number and subtypes of neurons derived from neural progenitor cells. However, our understanding of the proliferation and differentiation of neural progenitor cells is limited. COUP-TFI and -TFII genes, encoding two nuclear receptors, are associated with neurodevelopmental disease and heart defects respectively. Seven-up, the homologous gene of COUP-TF gene in Drosophila, is expressed and required in photoreceptor cell precursors. We observed that along dorso-ventral axis, COUP-TFI and -TFII genes are differentially expressed in mouse retinal stem cells. Minor defects in the eye are generated in either COUP-TFI or -TFII single gene knockout mouse with RXCre. Interestingly, loss of both genes in the retinal stem cells leads to failed differentiation of photoreceptors and thinner retina. The reduced bipolar cells, amacrine cells, horizontal cells, and ganglionic cells are also displayed in the double mutant retina. In addition, the development of Muller cells is repressed accompanying with fibrosis. Mechanistic studies reveal that COUP-TF genes may regulate the differentiation of photoreceptors through Crx and Nrl genes, and modulate the proliferation of retinal stem cells through P27 and P57 genes. Thus, our study shed new light on the understanding of evolutionarily conserved function of COUP-TF genes in the differentiation of photoreceptor cells.