Components of the Notch signaling pathway are essential for the development of numerous cell types during embryogenesis. Furthermore, mutations in Notch signaling components are associated with a variety of human diseases, including those affecting cardiovascular function. Within the vascular system, Notch receptors are expressed specifically in arterial endothelial cells and play a crucial role in defining artery identity. Notch signaling is also important for coordinating tip and stalk cell behaviors during th sprouting of new blood vessels, or angiogenesis. Our previous work using the zebrafish as a model system was instrumental in defining the roles of Notch during both artery differentiation and angiogenesis. Importantly, our past and current studies suggest that these are distinct processes governed through different receptor and ligand combinations. Additionally, Notch activation during these processes is dynamic, occurring at different developmental stages and in different endothelial subtypes. Thus, it is likely that there are distinct cellular outputs and morphogenetic responses controlled by Notch in each of these contexts. However, what the target genes are to mediate Notch function in different contexts is not known. To identify functional Notch targets in the vascular system, we propose studies encompassed in two separate Aims.
In Aim 1, we will investigate the requirements of candidate transcriptional repressors that we have found are dependent on Notch in arterial endothelial cells in zebrafish. These studies will rely on the application of site-specific nucleases to generate knockout zebrafish lines deficient for these genes, followed by detailed phenotypic and epistasis analysis. These studies will leverage our vast expertise using the zebrafish for complex genetic analyses coupled with high content phenotypic analysis.
In Aim 2, we will identify direct targets of the NOTCH1 receptor in human arterial endothelial cells to better understand how Notch activation programs artery identity. Taken together, these studies will allow us to understand how Notch may effect endothelial cell behaviors and differentiation in distinct contexts.
In the circulatory system, Notch receptors are required to define artery identity and to form new functional blood vessels. Mutations in Notch receptors are associated with congenital vascular diseases, including aortic valve calcification and CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a congenital syndrome associated with early-onset stroke. Our proposed studies will allow us to determine how Notch receptors control blood vessel identity and formation, which will provide new insights into their role in vascular disease.
|Hasan, Sana S; Tsaryk, Roman; Lange, Martin et al. (2017) Endothelial Notch signalling limits angiogenesis via control of artery formation. Nat Cell Biol 19:928-940|
|Lawson, Nathan D (2017) A New Conserved Player in Lymphatic Morphogenesis. Circ Res 120:1216-1218|
|Quillien, Aurelie; Abdalla, Mary; Yu, Jun et al. (2017) Robust Identification of Developmentally Active Endothelial Enhancers in Zebrafish Using FANS-Assisted ATAC-Seq. Cell Rep 20:709-720|
|Shin, Masahiro; Male, Ira; Beane, Timothy J et al. (2016) Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors. Development 143:3785-3795|
|Shin, Masahiro; Beane, Timothy J; Quillien, Aurelie et al. (2016) Vegfa signals through ERK to promote angiogenesis, but not artery differentiation. Development 143:3796-3805|
|Quillien, Aurelie; Moore, John C; Shin, Masahiro et al. (2014) Distinct Notch signaling outputs pattern the developing arterial system. Development 141:1544-52|
|Dang, Lan T H; Lawson, Nathan D; Fish, Jason E (2013) MicroRNA control of vascular endothelial growth factor signaling output during vascular development. Arterioscler Thromb Vasc Biol 33:193-200|
|Villefranc, Jacques A; Nicoli, Stefania; Bentley, Katie et al. (2013) A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development. Development 140:1497-506|
|Nicoli, Stefania; Knyphausen, Carl-Philipp; Zhu, Lihua J et al. (2012) miR-221 is required for endothelial tip cell behaviors during vascular development. Dev Cell 22:418-29|
|Cheung, Isla D; Bagnat, Michel; Ma, Taylur P et al. (2012) Regulation of intrahepatic biliary duct morphogenesis by Claudin 15-like b. Dev Biol 361:68-78|
Showing the most recent 10 out of 16 publications