{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Delta‐like ligand 4 (DLL4) is a multifunctional transmembrane protein that, by engaging Notch receptors, regulates cell fate decisions in diverse biological systems. In the intestine, DLL4 is expressed by specialized niche cells (Paneth cells) that physically associate with Lgr5+ stem cells to provide essential Notch‐mediated signals required for stem cell maintenance and crypt homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the vasculature, DLL4 serves as a pivotal negative feedback regulator during angiogenesis. Induced by VEGF and modulated by β‐catenin/Wnt signaling, DLL4 expression in endothelial tip cells limits excessive sprouting by activating Notch in neighboring stalk cells; this restricts tip cell numbers and orchestrates proper vessel branching and arterial specification, as demonstrated in retinal models and during embryonic vascular remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": " In tumors, DLL4 expression is dynamically regulated by VEGF; its signaling is critical to the development of a well‐patterned, functional vasculature. Paradoxically, blockade or down‐modulation of DLL4 leads to increased, but nonproductive, vessel density accompanied by tumor hypoxia and growth inhibition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": " Furthermore, DLL4 function is dosage sensitive in the regulation of arterial identity and vascular remodeling during development, with haploinsufficiency causing arterial malformations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": " DLL4 also plays an essential role in the thymus where its expression on thymic epithelial cells triggers Notch1‐dependent lineage commitment of T cell progenitors, suppressing alternative B cell fates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " In addition, DLL4 levels can be modulated by intercellular transfer; for example, exosomes released from mesenchymal stem cells or tumor cells may convey miRNAs (such as miR‐125a) or directly transfer DLL4 protein to endothelial cells, thereby influencing tip cell formation and angiogenic outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Finally, efficient endocytosis and processing of DLL4 by the E3 ubiquitin ligase Mib1 is essential for its activity in triggering Notch signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", and DLL4 induction is observed during the conversion of adult pancreatic duct cells into insulin‐expressing endocrine cells, highlighting its broader developmental significance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Toshiro Sato, Johan H van Es, Hugo J Snippert, et al. 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