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, since this knowledge may be relevant for future therapeutic applications.

Outline

I. Introduction: Elements of the Notch signaling pathway

II. Notch in vertebrate CNS development

II.1. Notch promotes progenitor diversification and inhibits neuronal differentiation

II. 2. Notch in gliogenesis

III. Notch in somitogenesis

IV. Notch in cardiovascular development

V. Notch in pancreas, gut endocrine and bone endocrine development

V.1. Pancreatic development

V.2. Gut development

V3. Bone development

VI. Notch in cancer

VI.1. Notch in hematological tumors

VI.2. Notch as an oncogene in solid tumors: breast and gut cancer

VI.3. Differential roles of NOTCH in two types of skin cancers: keratinocyte- derived carcinoma and melanomas

VI.4. Notch in EMT and tumor progression

VII. Concluding remarks

I. Introduction: Elements of the Notch signaling pathway