Notch: a mastermind of vascular morphogenesis
Leonard M. Anderson, Gary H. Gibbons
Leonard M. Anderson, Gary H. Gibbons
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):299-302. https://doi.org/10.1172/JCI31288.
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Category: Commentary

Notch: a mastermind of vascular morphogenesis

Abstract

The way in which multiple cell types organize themselves into a carefully sculpted, 3D labyrinth of vessels that regulate blood flow throughout the body has been a longstanding mystery. Clinicians familiar with congenital cardiovascular disease recognize how genetic variants and modest perturbations in this complex set of spatiotemporal interactions and stochastic processes can result in life-threatening anomalies. Although the mystery is not yet fully solved, we are poised at an exciting juncture, as insights from murine disease models are converging with advances in human genetics to shed new light on puzzling clinical phenotypes of vascular disease. The study by High et al. in this issue of the JCI establishes a model system that mimics clinical features of congenital cardiovascular disease and further defines the role of the Notch signaling pathway in the neural crest as an essential determinant of cardiovascular structure (see the related article beginning on page 353).

Authors

Leonard M. Anderson, Gary H. Gibbons

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Figure 1

Schematic representation of Notch signaling in neural crest cells that differentiate into VSMCs within the aortic arch during embryonic development.

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Schematic representation of Notch signaling in neural crest cells that d...
Notch receptors are transmembrane proteins that can transduce cell-cell interactions into cell fate determinations. Upon the binding of Notch to a ligand such as Jagged or Delta, the Notch carboxyterminal fragment is cleaved between Gly1743 and Val1744 by a γ-secretase. The cleaved intracellular domain translocates to the nucleus to form a heterocomplex with the transcription factor RBP-Jκ and coactivators such as MAML, resulting in transactivation of target effector genes (e.g., HES and HERP). The study by High et al. (6) in this issue of the JCI supports the model illustrated in this schema in which cell contact may occur between adjacent endothelial or neural crest cells to initiate VSMC lineage commitment through Notch-induced lateral specification. Downstream activation of target genes results in SMC lineage commitment by: (a) activation of known “master regulators” of VSMC differentiation (e.g., myocardin, myocardin-related transcription factors [MRTFs], or serum response factor [SRF]); (b) direct activation of contractile protein expression (e.g., smooth muscle myosin heavy chain [Sm-mhc]); or (c) activation of unknown effectors that can transactivate expression of genes in scenarios a and b (19, 20). Sm22α, smooth muscle protein 22–α.