SUMMARY The transcriptional regulation of neuroectoderm (NE) specification is unknown. Here we show that Pax6 is uniformly expressed in early NE cells of human fetuses and those differentiated from human embryonic stem cells (hESCs). This contrasts the later expression of Pax6 in restricted mouse brain regions. Knockdown of Pax6 blocks NE specification from hESCs. Overexpression of either Pax6a or Pax6b, but not Pax6 PD, triggers hESC differentiation. However, only Pax6a converts hESCs to NE. In contrast, neither loss nor gain of function of Pax6 affects mouse NE specification. Both Pax6a and Pax6b bind to pluripotent gene promoters but only Pax6a binds to NE genes during human NE specification. These findings indicate that Pax6 is a transcriptional determinant of the human NE and suggest that Pax6a and Pax6b coordinate with each other in determining the transition from pluripotency to the NE fate in human by differentially targeting pluripotent and NE genes.

The retinoblastoma (Rb) gene was the first tumour suppressor identified. Inactivation of Rb in mice results in unscheduled cell proliferation, apoptosis and widespread developmental defects, leading to embryonic death by day 14.5 (refs 2-4). However, the actual cause of the embryonic lethality has not been fully investigated. Here we show that loss of Rb leads to excessive proliferation of trophoblast cells and a severe disruption of the normal labyrinth architecture in the placenta. This is accompanied by a decrease in vascularization and a reduction in placental transport function. We used two complementary techniques-tetraploid aggregation and conditional knockout strategies-to demonstrate that Rb-deficient embryos supplied with a wild-type placenta can be carried to term, but die soon after birth. Most of the neurological and erythroid abnormalities thought to be responsible for the embryonic lethality of Rb-null animals were virtually absent in rescued Rb-null pups. These findings identify and define a key function of Rb in extra-embryonic cell lineages that is required for embryonic development and viability, and provide a mechanism for the cell autonomous versus non-cell autonomous roles of Rb in development.

Studies of the spin and parity quantum numbers of the Higgs boson are presented, based on proton–proton collision data collected by the ATLAS experiment at the LHC. The Standard Model spin–parity JP=0+JP=0+ hypothesis is compared with alternative hypotheses using the Higgs boson decays H→γγH→γγ, H→ZZ⁎→4ℓH→ZZ⁎→4ℓ and H→WW⁎→ℓνℓνH→WW⁎→ℓνℓν, as well as the combination of these channels. The analysed dataset corresponds to an integrated luminosity of 20.7 fb−1 collected at a centre-of-mass energy of √s=8TeV. For the H→ZZ⁎→4ℓH→ZZ⁎→4ℓ decay mode the dataset corresponding to an integrated luminosity of 4.6 fb−1 collected at √s=7TeV is included. The data are compatible with the Standard Model JP=0+JP=0+ quantum numbers for the Higgs boson, whereas all alternative hypotheses studied in this Letter, namely some specific JP=0−,1+,1−,2+JP=0−,1+,1−,2+ models, are excluded at confidence levels above 97.8%. This exclusion holds independently of the assumptions on the coupling strengths to the Standard Model particles and in the case of the JP=2+JP=2+ model, of the relative fractions of gluon-fusion and quark–antiquark production of the spin-2 particle. The data thus provide evidence for the spin-0 nature of the Higgs boson, with positive parity being strongly preferre

The homeobox gene Prox1 is crucial for mammalian lymphatic vascular development. In the absence of Prox1, lymphatic endothelial cells (LECs) are not specified. The maintenance of LEC identity also requires the constant expression of Prox1. However, the mechanisms controlling the expression of this gene in LECs remain poorly understood. The SRY-related gene Sox18 is required to induce Prox1 expression in venous LEC progenitors. Although Sox18 is also expressed in embryonic arteries, these vessels do not express Prox1, nor do they give rise to LECs. This finding suggests that some venous endothelial cell-specific factor is required for the activation of Prox1. Here we demonstrate that the nuclear hormone receptor Coup-TFII is necessary for the activation of Prox1 in embryonic veins by directly binding a conserved DNA domain in the regulatory region of Prox1. In addition, we show that the direct interaction between nuclear hormone receptors and Prox1 is also necessary for the maintenance of Prox1 expression during early stages of LEC specification and differentiation.[Keywords: Lymphatics; Prox1; Coup-TFII; mouse; endothelial cell] Supplemental material is available at http://www.genesdev.org.

The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease.