DLL4 (Delta-like protein 4) is a transmembrane ligand for Notch receptors belonging to the Delta/Serrate/Lag-2 (DSL) family. It plays critical roles in vascular development, neural progenitor cell fate determination, and synaptic plasticity. DLL4-Notch signaling is a key pathway in neurovascular unit function and has been increasingly implicated in neurodegenerative processes including Alzheimer's disease, stroke, and traumatic brain injury.
DLL4 (Delta-like protein 4) is a transmembrane ligand for Notch receptors belonging to the Delta/Serrate/Lag-2 (DSL) family. It plays critical roles in vascular development, neural progenitor cell fate determination, and synaptic plasticity. DLL4-Notch signaling is a key pathway in neurovascular unit function and has been increasingly implicated in neurodegenerative processes including Alzheimer's disease, stroke, and traumatic brain injury.
Overview
DLL4 is a type I transmembrane protein that functions as a potent regulator of Notch receptor signaling. While best characterized for its essential role in developmental and pathological angiogenesis, emerging research has revealed important functions in the central nervous system. In the brain, DLL4 is expressed primarily in endothelial cells lining cerebral vasculature, where it regulates neurovascular coupling and [blood-brain barrier](/entities/blood-brain-barrier) (BBB) integrity. Additionally, DLL4-Notch signaling influences neural stem cell proliferation, differentiation, and survival in both embryonic and adult neurogenic niches. [@zhang2010]
The DLL4-Notch axis has become a focal point in neurodegeneration research due to its dual roles in vascular health and neural progenitor cell regulation. In Alzheimer's disease, alterations in DLL4 expression contribute to neurovascular dysfunction, impaired amyloid clearance, and dysregulated adult neurogenesis. Therapeutic modulation of DLL4-Notch signaling represents an active area of investigation for neuroprotective strategies, though careful consideration of the pathway's context-dependent effects is essential. [@brtsch2013]
Structure
DLL4 is a 685 amino acid protein containing: [@fan2024]
[Benedito R, et al., Synchronization of endothelial Dll4-Notch dynamics switches blood vessels from branching to expansion (2016) (2016)](/PMID: 27074663(https://pubmed.ncbi.nlm.nih.gov/27074663/))
[Zhang Y, et al., Notch-1 signalling is activated in brain arteriovenous malformations in humans (2010) (2010)](/PMID: 19812212(https://pubmed.ncbi.nlm.nih.gov/19812212/))
[Brütsch R, et al., Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in cerebral cavernous malformations (2013) (2013)](/PMID: 23388056(https://pubmed.ncbi.nlm.nih.gov/23388056/))
[Fan Y, et al., DLL4 regulates cerebrovascular development and endothelial integrity via Notch-CLDN5 pathway (2024) (2024)](/PMID: 38632887(https://pubmed.ncbi.nlm.nih.gov/38632887/))
[Lee YJ, et al., The Vascular Notch Ligands Delta-Like Ligand 4 (DLL4) and Jagged1 have opposing correlations with microvascularization in primary glioblastoma (2015) (2015)](/PMID: 26546995(https://pubmed.ncbi.nlm.nih.gov/26546995/))