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Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVβ8 activates angiosuppressive TGFβ gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVβ8 in the brain or downstream TGFβ1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb(ret/ret) mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.

Frizzled (Fz) receptors have been implicated in the reception of diverse Wnt ligands during vertebrate and invertebrate development. Wnt-Fz signals can induce changes in gene expression mediated by b-catenin/TCF controlled transcriptional events (also referred to as canonical Wnt signaling). In addition, recent evidence has indicated that members of the Fz receptor family can also signal through other intracellular pathways distinct from b-catenin/TCF transcriptional regulation (non-canonical Wnt signaling). In Drosophila, Fz and Fz2 act as redundant receptors for Wg during development by activating the canonical Wnt cascade. Fz, in addition, organizes planar polarization of epithelial structures through a small GTPase/JNK pathway. We are addressing how Fz and Fz2 specifically activate these distinct signaling pathways, and how the common Fz effector Dishevelled (Dsh) can transduce the signal(s) into these distinct cascades. We find that Fz2 activates canonical Wnt signaling, whereas Fz preferentially signals through the non-canonical planar polarity pathway. Chimeric receptors indicate that the critical domain for context-dependent signaling specificity maps to the C-terminal cytoplasmic tail. Similarly, different domains within Dsh are specifically required for the different signaling outcomes. The context specific signaling features of Fz and Dsh will be discussed.

Epidermal Growth Factor-receptor (Egfr) signaling is evolutionarily conserved and controls a variety of different cellular processes. In Drosophila these include proliferation, patterning, cell-fate determination, migration and survival. Here we provide evidence for a new role of Egfr signaling in controlling ommatidial rotation during planar cell polarity (PCP) establishment in the Drosophila eye. Although the signaling pathways involved in PCP establishment and photoreceptor cell-type specification are beginning to be unraveled, very little is known about the associated 90° rotation process. One of the few rotation-specific mutations known is roulette (rlt) in which ommatidia rotate to a random degree, often more than 90°. Here we show that rlt is a rotation-specific allele of the inhibitory Egfr ligand Argos and that modulation of Egfr activity shows defects in ommatidial rotation. Our data indicate that, beside the Raf/MAPK cascade, the Ras effector Canoe/AF6 acts downstream of Egfr/Ras and provides a link from Egfr to cytoskeletal elements in this developmentally regulated cell motility process. We provide further evidence for an involvement of cadherins and nonmuscle myosin II as downstream components controlling rotation. In particular, the involvement of the cadherin Flamingo, a PCP gene, downstream of Egfr signaling provides the first link between PCP establishment and the Egfr pathway. [ABSTRACT FROM AUTHOR]