Toward identifying the roles of protease-activated receptor-1 (PAR1) and other G protein-coupled receptors important for vascular development, we investigated the role of G␣ 13 in endothelial cells in the mouse embryo. LacZ inserted into G␣13 exon 1 was highly expressed in endothelial cells at midgestation. Endothelialspecific G␣13 knockout embryos died at embryonic days 9.5-11.5 and resembled the PAR1 knockout. Restoration of G␣ 13 expression in endothelial cells by use of a Tie2 promoter-driven G␣13 transgene rescued development of endothelial-specific G␣ 13 knockout embryos as well the embryonic day 9.5 vascular phenotype in G␣ 13 conventional knockouts; transgene-positive G␣13 ؊/؊ embryos developed for several days beyond their transgene-negative G␣ 13 ؊/؊ littermates and then manifested a previously uncharacterized phenotype that included intracranial bleeding and exencephaly. Taken together, our results suggest a critical role for G␣ 13 in endothelial cells during vascular development, place G␣13 as a candidate mediator of PAR1 signaling in this process, and reveal roles for G␣ 13 in other cell types in the mammalian embryo.F ormation of blood vessels during mammalian embryonic development is a complex and highly regulated process. Angioblasts proliferate, migrate, and differentiate to form primitive vascular structures composed of endothelial cells. These structures remodel by sprouting, branching, growing, and regressing, and mature by the recruitment and differentiation of pericytes and smooth muscle cells (1-3). Studies to define the molecular signals that orchestrate vascular development have focused mainly on receptor tyrosine kinases and integrins and their ligands (1,(4)(5)(6)(7)(8)(9). Less is known regarding the roles of G protein-coupled receptors (GPCRs) in this process (10-16).Protease-activated receptor-1 (PAR1), a GPCR for thrombin, plays an important role in the formation and͞or maintenance of blood vessels in mouse embryos, a role likely attributable to PAR1 function in endothelial cells (11,14). PAR1 triggers a host of cellular responses through heterotrimeric G proteins of the Gq͞11, Gi͞o, and G12͞13 families; which of these pathways is important for proper vascular development is unknown. Conventional knockout of the gene-encoding G␣ 13 caused death of mouse embryos at midgestation with a phenotype grossly similar to, but more penetrant than, the PAR1 phenotype (17). We report a key role for G␣ 13 in endothelial cells at midgestation, suggesting that loss of G␣ 13 signaling in endothelial cells may account for the embryonic phenotype associated with PAR1 deficiency. Our results also unmask roles for G␣ 13 in other cell types. Materials and Methods Mutant Mouse Strains. Generation of the G␣13-lacZ knockin allele.Gna13 (herein designated G␣ 13 ) gene fragments from a bacterial artificial chromosome from a 129͞SvJ mouse genomic library, along with the lacZ gene, were used to construct a G␣ 13 -lacZ knockin allele as described in Supporting Methods, which is published as supporting informat...

Scholars focusing on court-agency relationships at the federal level have generally neglected the role played by the courts of appeals. Exploring agency cases coming before the Court of Appeals for the District of Columbia (1981)(1982)(1983)(1984), this analysis reveals fairly strong support for the positions of federal agencies taken as a whole. Considerable variance, however, exists across both individual judges and specific agencies. Although much of the variance remains unaccounted for, the political environment of each agency sampled and the background characteristics of the court's judges provide a partial explanation. Of the individual background attributes isolated, party affiliation appears to have the most significance, with Republican judges displaying the highest levels of agency support.

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