COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis

Abstract

SUMMARYTranscriptional networks, which are initiated by secreted proteins, cooperate with each other to orchestrate eye development. The establishment of dorsal/ventral polarity, especially dorsal specification in the optic vesicle, is poorly understood at a molecular and cellular level. Here, we show that COUP-TFI (Nr2f1) and COUP-TFII (Nr2f2) are highly expressed in the progenitor cells in the developing murine eye. Phenotype analysis of COUP-TFI and COUP-TFII single-gene conditional knockout mouse models suggests that COUP-TFs compensate for each other to maintain morphogenesis of the eye. However, in eye-specific COUP-TFI/TFII doubleknockout mice, progenitor cells at the dorso-distal optic vesicle fail to differentiate appropriately, causing the retinal pigmented epithelium cells to adopt a neural retina fate and abnormal differentiation of the dorsal optic stalk; the development of proximoventral identities, neural retina and ventral optic stalk is also compromised. These cellular defects in turn lead to congenital ocular colobomata and microphthalmia. Immunohistochemical and in situ hybridization assays reveal that the expression of several regulatory genes essential for early optic vesicle development, including Pax6, Otx2, Mitf, Pax2 and Vax1/2, is altered in the corresponding compartments of the mutant eye. Using ChIP assay, siRNA treatment and transient transfection in ARPE-19 cells in vitro, we demonstrate that Pax6 and Otx2 are directly regulated by COUP-TFs. Taken together, our findings reveal novel and distinct cell-intrinsic mechanisms mediated by COUP-TF genes to direct the specification and differentiation of progenitor cells, and that COUP-TFs are crucial for dorsalization of the eye.

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

“…S14A). Because Coup-TF2 has overlapping functions with Coup-TF1 (Tang et al, 2010), we sensitized the Coup-TF2 mutants using a Coup-TF1 − allele. Mutants were generated using the following cross: Coup-TF1 +/− ; .…”

COUP-TFII controls amygdala patterning by regulating neuropilin expression

“…COUP-TFII (Nr2f2 -Mouse Genome Informatics), an orphan nuclear receptor, is essential for the morphogenesis of multiple organs (Takamoto et al, 2005a;Takamoto et al, 2005b;You et al, 2005a;You et al, 2005b;Kurihara et al, 2007;Petit et al, 2007;Li et al, 2009;Kim et al, 2009;Tang et al, 2010;Lin et al, 2010). In this study, we found that COUP-TFII was strongly expressed in the CGE, and we generated a conditional mutant that eliminated COUP-TFII function in the ventral telencephalon with RxCre.…”

Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb

“…hGFAP-Cre mice (Zhuo et al, 2001), Emx1-Cre (Gorski et al, 2002) and Nestin-CreER mice (Lagace et al, 2007) were obtained from the Jackson Laboratory. COUP-TFI flox/flox and COUP-TFII flox/flox mice were genotyped as previously described (Takamoto et al, 2005;Tang et al, 2010). Mice used in this study were of mixed background.…”