ABSTRACT
Every organ in the body requires blood vessels for efficient delivery of oxygen and nutrients, but independent vascular beds are highly specialized to meet the individual needs of specific organs. The vasculature of the brain is tightly sealed, with blood-brain barrier (BBB) properties developing coincident with neural vascularization. G protein-coupled receptor 124 (GPR124) (tumor endothelial marker 5, TEM5), an orphan member of the adhesion family of G protein-coupled receptors, was previously identified on the basis of its overexpression in tumor vasculature. Here, we show that global deletion or endothelial-specific deletion of GPR124 in mice results in embryonic lethality associated with abnormal angiogenesis of the forebrain and spinal cord. Expression of GPR124 was found to be required for invasion and migration of blood vessels into neuroepithelium, establishment of BBB properties, and expansion of the cerebral cortex. Thus, GPR124 is an important regulator of neurovasculature development and a potential drug target for cerebrovascular diseases.
Subject(s)
Blood-Brain Barrier/embryology , Central Nervous System/blood supply , Central Nervous System/embryology , Embryo, Mammalian/blood supply , Receptors, G-Protein-Coupled/physiology , Animals , Blood-Brain Barrier/metabolism , Blotting, Western , DNA Primers/genetics , Embryo, Mammalian/metabolism , Flow Cytometry , Histological Techniques , In Situ Hybridization , Mice , Microscopy, Electron , Microscopy, Fluorescence , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Tumor endothelial marker 8 (TEM8) was initially identified as a gene overexpressed in the vasculature of human tumors and was subsequently identified as an anthrax toxin receptor. To assess the functional role of TEM8, we disrupted the TEM8 gene in mice by targeted homologous recombination. TEM8(-/-) mice were viable and reached adulthood without defects in physiologic angiogenesis. However, histopathologic analysis revealed an excess of extracellular matrix in several tissues, including the ovaries, uterus, skin, and periodontal ligament of the incisors, the latter resulting in dental dysplasia. When challenged with B16 melanoma, tumor growth was delayed in TEM8(-/-) mice, whereas the growth of other tumors, such as Lewis lung carcinoma, was unaltered. These studies show that host-derived TEM8 promotes the growth of certain tumors and suggest that TEM8 antagonists may have utility in the development of new anticancer therapies.
Subject(s)
Melanoma, Experimental/pathology , Receptors, Peptide/physiology , Animals , Biomarkers, Tumor , Carcinoma, Lewis Lung/blood supply , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Female , Male , Melanoma, Experimental/blood supply , Melanoma, Experimental/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Microfilament Proteins , Neovascularization, Pathologic/pathology , Receptors, Cell Surface , Receptors, Peptide/biosynthesis , Receptors, Peptide/deficiency , Receptors, Peptide/geneticsABSTRACT
The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Delta32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Delta32 arose within the past 1,000 y and rose to its present high frequency (5%-14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Delta32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Delta32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen at CCR5-Delta32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome.
