The study by High et al. (6
) provides compelling evidence that neural crest–directed blockade of Notch signaling with a dominant-negative MAML
gene construct inhibits VSMC differentiation and results in aortic patterning defects reminiscent of clinical phenotypes. However, a limitation of this approach is the potential for forced expression of dominant-negative constructs to yield spurious results due to “off-target” effects that may extend beyond the Notch pathway. In fact, recent reports indicate that MAML can also act as a coactivator of myocyte enhancer factor 2C (MEF2C) (18
), a well-established mediator of cardiovascular morphogenesis. It remains an open question which additional pathways are engaged in parallel to Notch and what downstream effectors mediate the direct coupling of Notch signaling to VSMC differentiation programs. In addition, the current model fails to reconcile the conflicting data derived from in vitro models that suggest that Notch signaling may inhibit myocardin-induced VSMC differentiation (19
). Unfortunately, a common limitation of these in vitro studies is the failure to capture the subtle physiologic interplay among epigenetics, coactivator/corepressor complexes that exist in vivo, and the combinatorial effect of several downstream Notch effectors working in concert to orchestrate the VSMC differentiation program. It is becoming clear that the capacity of Notch to elicit lineage specification in a wide spectrum of developmental processes reflects the exquisite sensitivity of the pathway to the local milieu and the combinatorial interplay with other elements of the gene regulatory network peculiar to a given cellular context. The in vivo model used by High and colleagues captures the complex nuances of these gene regulatory circuits and provides a way forward toward the identification of novel downstream mediators of the Notch pathway in VSMC differentiation.
It is anticipated that the growing application of genomic approaches to define signature patterns in gene expression profiles during lineage commitment will lead to the discovery of new members of the vascular development gene regulatory network, advancing our understanding of human disease (21
). This convergence of genomic strategies is exemplified by the recent discovery that mutations in the TGF-β signaling pathway (a key mediator in the vascular development gene circuitry) result in a newly defined form of aortic disease (Loeys-Dietz syndrome) (22
), and may foster a novel therapeutic strategy for adult vascular disease (23
). Likewise, the growing integration of systems biology approaches (21
) into the analysis of cardiovascular development holds promise for unlocking the remaining mysteries of the complex gene regulation circuitry governing vascular morphogenesis.