Macrophage type-I and type-II class-A scavenger receptors (MSR-A) are implicated in the pathological deposition of cholesterol during atherogenesis as a result of receptor-mediated uptake of modified low-density lipoproteins (mLDL). MSR-A can bind an extraordinarily wide range of ligands, including bacterial pathogens, and also mediates cation-independent macrophage adhesion in vitro. Here we show that targeted disruption of the MSR-A gene in mice results in a reduction in the size of atherosclerotic lesions in an animal deficient in apolipoprotein E. Macrophages from MSR-A-deficient mice show a marked decrease in mLDL uptake in vitro, whereas mLDL clearance from plasma occurs at a normal rate, indicating that there may be alternative mechanisms for removing mLDL from the circulation. In addition, MSR-A-knockout mice show an increased susceptibility to infection with Listeria monocytogenes or herpes simplex virus type-1, indicating that MSR-A may play a part in host defence against pathogens.

The endothelin-1 (ET-1) gene was disrupted in mouse embryonic stem cells by homologous recombination to generate mice deficient in ET-1. These ET-1-/- homozygous mice die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs. ET-1+/- heterozygous mice, which produce lower levels of ET-1 than wild-type mice, develop elevated blood pressure. These results suggest that ET-1 is essential for normal mouse development and may also play a physiological role in cardiovascular homeostasis.

Recently, roles of Delta-like 4 (Dll4)-Notch signaling in angiogenesis have been demonstrated by a series of reports (Ridgway et al., 2006;Hellstrom et al., 2007;Siekmann and Lawson, 2007;Suchting et al., 2007). Murine retina heterozygous for a null mutation of the Dll4 gene showed excessive branching and this was recapitulated by administering a -secretase inhibitor, Development 138, 4763-4776 (2011Development 138, 4763-4776 ( ) doi:10.1242 SUMMARYAngiogenesis is a complex process, which is accomplished by reiteration of modules such as sprouting, elongation and bifurcation, that configures branching vascular networks. However, details of the individual and collective behaviors of vascular endothelial cells (ECs) during angiogenic morphogenesis remain largely unknown. Herein, we established a time-lapse imaging and computer-assisted analysis system that quantitatively characterizes behaviors in sprouting angiogenesis. Surprisingly, ECs moved backwards and forwards, overtaking each other even at the tip, showing an unknown mode of collective cell movement with dynamic 'cell-mixing'. Mosaic analysis, which enabled us to monitor the behavior of individual cells in a multicellular structure, confirmed the 'cell-mixing' phenomenon of ECs that occurs at the whole-cell level. Furthermore, an in vivo EC-tracking analysis revealed evidence of cell-mixing and overtaking at the tip in developing murine retinal vessels. In parametrical analysis, VEGF enhanced tip cell behavior and directed EC migration at the stalk during branch elongation. These movements were counter-regulated by EC-EC interplay via -secretase-dependent Dll4-Notch signaling, and might be promoted by EC-mural cell interplay. Finally, multiple regression analysis showed that these molecule-mediated tip cell behaviors and directed EC migration contributed to effective branch elongation. Taken together, our findings provide new insights into the individual and collective EC movements driving angiogenic morphogenesis. The methodology used for this analysis might serve to bridge the gap in our understanding between individual cell behavior and branching morphogenesis.

Numerous immature thymocytes undergo apoptosis and are rapidly engulfed by phagocytic thymic macrophages. The macrophage surface receptors involved in apoptotic thymocyte recognition are unknown. We have examined the role of the class A macrophage scavenger receptor (SR-A) in the engulfmnent of apoptotic thymocytes. Uptake of steroid-treated apoptotic thymocytes by thymic and inflammatory-elicited SR-A positive macrophages is partially inhibited by an anti-SR-A mAb and more completely by a range of scavenger receptor ligands. Thymic macrophages from mice with targeted disruption of the SR-A gene show a 50% reduction in phagocytosis of apoptotic thymocytes in vitro. These data suggest that SR-A may play a role in the clearance of dying cells in the thymus.Apoptosis or programmed cell death is now recognized as the physiologic mechanism by which large numbers of unwanted cells are deleted from the body (1). However, examination of tissues with ongoing programmed cell death highlights the scant evidence of dying cells in situ, a paradox that is explained by the existence of mechanisms for the specific and rapid removal of apoptotic cells by phagocytes. One of the earliest markers of commitment to undergo programmed cell death is phagocytosis of the apoptotic cell. In contrast to our knowledge of the process of apoptosis itself, relatively little is known of the clearance process by which dying cells are removed from the body in a manner that has no apparent inflammatory consequence. Examination of apoptotic cells in situ has shown that they are taken up and degraded by phagocytes, in particular macrophages (M+) (2). This activity can be observed in MO-like cells from species such as Drosophila, suggesting this is an important and conserved process (3) The process is specific, in that only cells committed to die are phagocytosed, and rapid, so that uptake is completed before the integrity of the apoptotic cell membrane is lost. Two essential components are required for the successful ingestion of the apoptotic cells: (i) specific receptor(s) on the surface of the phagocyte to mediate rapid recognition and ingestion and (ii) the presence of appropriate ligands on apoptotic cells that permit their distinction from healthy neighbors. The consensus that can be drawn from the relatively small number of reported studies on apoptotic cell recognition is that just like the regulation of apoptosis itself, it is complex and that there is not a single receptor-ligand system that explains apoptotic cell removal by all phagocytes (4).The thymus is the organ where the repertoire of mature T cells is selected from a much larger number of immature thymocytes and extensive apoptotic cell death occurs in the immature thymocyte populations. Although numerous immature thymocytes undergo apoptosis (5-7), few dead cells are observed in situ due to rapid engulfment by phagocytic M4 in the thymic stroma (8-10). A recent study (11), using the sensitive terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL) technique ...

H. Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ.