Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development

• DOI: 10.1073/pnas.1300805110
• Publication Date: 2013-07-02T04:42:22Z
• Authors: Natalia Sacilotto; Rui Monteiro; Martin Fritzsche; Philipp W. Becker; Luis Sanchez-del-...; Ke Liu; Philip Pinheiro; Indrika Ratnayaka; Benjamin Davies; Colin R. Goding; Roger Patient; George Bou-Gharios; Sarah De Val
• Keywords: Cell fate determination

The mechanisms by which arterial fate is established and maintained are not clearly understood. Although a number of signaling pathways transcriptional regulators have been implicated in arterio-venous differentiation, none essential for formation, the manner widely expressed factors may achieve arterial-specific gene regulation unclear. Using both mouse zebrafish models, we demonstrate here that specification regulated combinatorially Notch SoxF transcription factors, via direct activation. Through identification characterization two endothelial cell-specific enhancers ligand Delta-like 4 (Dll4) , show Dll4 expression requires binding RBPJ/Notch intracellular domain SOXF factors. Specific combinatorial, but individual, loss RBPJ DNA ablates all enhancer-transgene despite presence multiple functional ETS sites, as does knockdown sox7 ; sox18 combination with signaling. Furthermore, triple rbpj also results ablation endogenous dll4 expression. Fascinatingly, this combinatorial leads to markers absence detectable dorsal aorta, demonstrating roles Notch, together, acquisition identity.