Summary Sprouting angiogenesis expands the embryonic vasculature enabling survival and homeostasis. Yet how the angiogenic capacity to form sprouts is allocated among endothelial cells (ECs) to guarantee the reproducible anatomy of stereotypical vascular beds remains unclear. Here we show that Sema-PlxnD1 signaling, previously implicated in sprout guidance, represses angiogenic potential to ensure the proper abundance and stereotypical distribution of the trunk’s Segmental Arteries (SeAs). We find that Sema-PlxnD1 signaling exerts this effect by antagonizing the pro-angiogenic activity of Vascular Endothelial Growth Factor (VEGF). Specifically, Sema-PlxnD1 signaling ensures the proper endothelial abundance of soluble flt1 (sflt1), an alternatively spliced form of the VEGF receptor Flt1 encoding a potent secreted decoy. Hence Sema-PlxnD1 signaling regulates distinct but related aspects of angiogenesis: the spatial allocation of angiogenic capacity within a primary vessel and sprout guidance.

Sprouting angiogenesis expands the primitive vasculature of the embryo and its essential for survival and homeostasis. However, the mechanisms that allocate the capacity to form sprouts among endothelial cells to ensure the reproducible anatomy of stereotypical vascular beds remain unknown. Using the zebrafish model system, confocal imaging, RNA in situ hybridization, cell transplantation/ competition experiments and both loss and gain-of-function approaches here we show that Sema-PlxnD1 signaling, previously implicated in sprout guidance, plays precisely this role. Molecularly, Sema-PlxnD1 signaling exerts this effect by modulating the effects of other vascular development pathways.Program/Abstract # 2 Specialized ribosomes control Hox mRNA translation and vertebrate tissue patterning Control of gene expression in space and time plays an important role in enabling cells to "know" where they are in the developing vertebrate embryo and what to become. Decades of research have demonstrated numerous layers of regulation in gene expression that coordinate this process, although translational control has received less experimental attention. Here we unexpectedly show that a single component of the ribosome establishes the mammalian body plan. Our data reveal that mutations of the Ribosomal Protein L38 (Rpl38) gene in mice lead to tissue specific patterning defects, including pronounced homeotic transformations of the axial skeleton. By optimizing genetic and molecular approaches to study translational regulation within the vertebrate embryo, we uncover an important role for RPL38 in transcript-specific translational control. In Rpl38 mutant embryos, global protein synthesis is unchanged however the translation of a select subset of Homeobox mRNAs is perturbed. Our data reveal that RPL38 facilitates 80S complex formation on these mRNAs as a regulatory component of the ribosome and uncover novel complexity in regulation of Hox gene expression at the level of translational control. We further show that Rpl38 expression is markedly enriched in regions of the embryo, such as somites, where lossof-function phenotypes occur. We extended these findings by performing an expression-profiling screen for the majority of the 79 ribosomal proteins associated with both small and large ribosome subunits. This analysis unexpectedly identified dynamic regulation in the expression of ribosomal proteins, which historically have been considered to be ubiquitously expressed housekeeping genes, within the vertebrate embryo. Collectively, these findings suggest that a "ribosomal protein code" established by distinct expression levels and translational specificity of ribosomal proteins may provide a new level of regulation in gene expression and mammalian development.To understand how secretory organs acquire their final form and function, we focus on a simple well-developed genetic system, the Drosophila salivary gland (SG). The SG is a simple tube that undergoes the same morphogenetic events that occur in organs of more complicated systems,...

The activation of tissue stem cells from their quiescent state represents the initial step in the complex process of organ regeneration and tissue repair. While the identity and location of tissue stem cells are becoming known, how key regulators control the balance of activation and quiescence remains mysterious. The vertebrate hair is an ideal model system where hair cycling between growth and resting phases is precisely regulated by morphogen signaling pathways, but how these events are coordinated to promote orderly signaling in a spatial and temporal manner remains unclear. Here, we show that hair cycle timing depends on regulated stability of signaling substrates by the ubiquitin-proteasome system. Topical application of partial proteasomal inhibitors (PaPIs) inhibits epidermal and dermal proteasome activity throughout the hair cycle. PaPIs prevent the destruction of the key anagen signal β-catenin, resulting in more rapid hair growth and dramati cally shortened telogen. We show that PaPIs induce excess β-catenin, act similarly to the GSK3β antagonist LiCl, and antagonize Dickopf-related protein-mediated inhibition of anagen. PaPIs thus represent a novel class of hair growth agents that act through transiently modifying the balance of stem cell activation and quiescence pathways.