Notch signaling in development and cancer.

Notch is an evolutionarily conserved local cell signaling mechanism that participates in a variety of cellular processes: cell fate specification, differentiation, proliferation, apoptosis, adhesion, epithelial-mesenchymal transition, migration, and angiogenesis. These processes can be subverted in Notch-mediated pathological situations. In the first part of this review, we will discuss the role of Notch in vertebrate central nervous system development, somitogenesis, cardiovascular and endocrine development, with attention to the mechanisms by which Notch regulates cell fate specification and patterning in these tissues. In the second part, we will review the molecular aspects of Notch-mediated neoplasias, where Notch can act as an oncogene or as a tumor suppressor. From all these studies, it becomes evident that the outcome of Notch signaling is strictly context-dependent and differences in the strength, timing, cell type, and context of the signal may affect the final outcome. It is essential to understand how Notch integrates inputs from other signaling pathways and how specificity is achieved, because this knowledge may be relevant for future therapeutic applications.

Notch signaling is essential for ventricular chamber development.

Ventricular chamber morphogenesis, first manifested by trabeculae formation, is crucial for cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. We show that ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, attenuated EphrinB2, NRG1, and BMP10 expression and signaling, and decreased myocardial proliferation. Functional and molecular analyses show that Notch inhibition prevents EphrinB2 expression, and that EphrinB2 is a direct Notch target acting upstream of NRG1 in the ventricles. However, BMP10 levels are found to be independent of both EphrinB2 and NRG1 during trabeculation. Accordingly, exogenous BMP10 rescues the myocardial proliferative defect of in vitro-cultured RBPJk mutants, while exogenous NRG1 rescues differentiation in parallel. We suggest that during trabeculation Notch independently regulates cardiomyocyte proliferation and differentiation, two exquisitely balanced processes whose perturbation may result in congenital heart disease.

Notch and epithelial-mesenchyme transition in development and tumor progression: another turn of the screw.

Notch is an ancient cell signaling system that regulates cell fate specification, stem cell maintenance and initiation of differentiation in embryonic and postnatal tissues.(1) Alteration of these functions in the adult have been associated to various types of cancer in which Notch may act as an oncogene or as a tumor suppressor. As occurs during development, Notch cooperates with other signaling pathways in the transformation process. Notch has recently been shown to promote epithelial-to-mesenchymal transition (EMT) during cardiac valve formation, via snail induction and subsequent cadherin downregulation. One implication of this work is that Notch acting through a similar mechanism, may also be involved in the EMT process that occurs during tumor progression and converts polarized epithelial cells into motile, invasive cells.

Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.

Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types. In the embryonic heart, Notch functions via lateral induction to promote a selective transforming growth factor-beta (TGFbeta)-mediated EMT that leads to cellularization of developing cardiac valvular primordia. Embryos that lack Notch signaling elements exhibit severely attenuated cardiac snail expression, abnormal maintenance of intercellular endocardial adhesion complexes, and abortive endocardial EMT in vivo and in vitro. Accordingly, transient ectopic expression of activated Notch1 (N1IC) in zebrafish embryos leads to hypercellular cardiac valves, whereas Notch inhibition prevents valve development. Overexpression of N1IC in immortalized endothelial cells in vitro induces EMT accompanied by oncogenic transformation, with corresponding induction of snail and repression of VE-cadherin expression. Notch is expressed in embryonic regions where EMT occurs, suggesting an intimate and fundamental role for Notch, which may be reactivated during tumor metastasis.