Vascular Branching Morphogenesis of the Placenta Requires Expression of Ott1(Rbm15) in the Trophoblast Compartment.

OTT1(RBM15) is a transcriptional activator/repressor known to be a fusion partner in t(1;22) infant acute megakaryocytic leukemia. Conditional deletion of Ott1 in adult mice resulted in expansions of the megakaryocytic, myeloid and pluripotent Lin⁻Sca-1⁺c-Kit⁺ populations and a block in pre B lymphoid development, suggesting a global regulatory role in hematopoiesis. Germline deletion of Ott1 is homozygous lethal after E9.5, producing developmentally delayed embryos with open notochords. Further investigation into the cause of embryonic death revealed a placental defect characterized by arrested vascular branching morphogenesis of the invading fetal vessels, leading to embryonic demise through inadequate oxygenation. Histopathology and in situ hybridization of Ott1-deficient placentas identified a dramatic reduction in the spongiotrophoblast and syncytiotrophoblast layers. Expression of Vegf, a critical element of placental vasculogenesis, was still observed, thus excluding the requirement for Ott1 in its induction. By using Sox2-cre with a conditional allele of Ott1, complete excision of Ott1 was achieved within the embryo yet the placental trophoblast compartment was left undeleted. These embryos were now able to form normal placentas with intact vascular branching morphogenesis and survive to term. This result demonstrates that Ott1-mediated vascular branching morphogenesis is regulated by the trophoblast compartment rather than the invading fetal vasculature. Additionally, the Sox2-cre-deleted pups manifested cardiac ventricular septal defects and hyposplenia and succumbed during the perinatal period. Hox, Notch and hypoxia-related pathways are important for both cardiac and splenic development, however downstream target gene expression was not perturbed. In summary, Ott1-dependent pathways, in addition to their implicit involvement in a congenital leukemia, are essential for vascular branching morphogenesis in the placenta and organogenesis of the mesoderm-derived heart, spleen and blood. Mutation of OTT1 or alterations in its regulation may therefore underlie human disorders such as placental insufficiency, asplenia or congenital cardiac malformations.