Nuclear receptor NR5A2 is required for proper primitive streak morphogenesis

Abstract

NR5A2, also known as liver receptor homologue 1 (LRH-1) and fetoprotein transcription factor (FTF), is an orphan nuclear receptor involved in the regulation of cholesterol metabolism and steroidogenesis in the adult. NR5A2 was also shown to be expressed during early mouse embryogenesis. Consistent with its early expression pattern, a targeted disruption of this gene leads to embryonic lethality around the gastrulation period. To characterize the embryonic phenotype resulting from NR5A2 loss of function, we undertook morphological and marker gene analyses and showed that NR5A2-/- embryos display growth retardation, epiblast disorganization, a mild embryonic-extraembryonic constriction, as well as abnormal thickening of the proximo-posterior epiblast. We demonstrated that, although initial specification of the anterior-posterior axis occurred in the absence of NR5A2, primitive streak formation was impaired and neither embryonic nor extraembryonic mesoderm was generated. Moreover, although the visceral endoderm does not show major morphological abnormalities in NR5A2-/- embryos, a decrease in the expression level of HNF4 and GATA4 was observed. Aggregation experiments demonstrated that, in the presence of wild-type tetraploid cells, NR5A2 mutant cells in the epiblast are capable of undergoing normal gastrulation. Therefore, our results suggest a requirement for NR5A2 in extraembryonic tissues and identify a novel role of this gene in proper primitive streak morphogenesis.