Understanding the Principles of Pattern Formation Driven by Notch Signaling by Integrating Experiments and Theoretical Models

Abstract

Notch signaling is an evolutionary conserved cell-cell communication pathway. Besides regulating cell-fate decisions at an individual cell level, Notch signaling coordinates the emergent spatiotemporal patterning in a tissue through ligand-receptor interactions among transmembrane molecules of neighboring cells, as seen in embryonic development, angiogenesis, or wound healing. Due to its ubiquitous nature, Notch signaling is also implicated in several aspects of cancer progression, including tumor angiogenesis, stemness of cancer cells and cellular invasion. Here, we review experimental and computational models that help understand the operating principles of cell patterning driven by Notch signaling. First, we discuss the basic mechanisms of spatial patterning via canonical lateral inhibition and lateral induction mechanisms, including examples from angiogenesis, inner ear development and cancer metastasis. Next, we analyze additional layers of complexity in the Notch pathway, including the effect of varying cell sizes and shapes, ligand-receptor binding within the same cell, variable binding affinity of different ligand/receptor subtypes, and filopodia. Finally, we discuss some recent evidence of mechanosensitivity in the Notch pathway in driving collective epithelial cell migration and cardiovascular morphogenesis.

Keywords: Delta; Jagged; Notch; cell-cell signaling; lateral induction; lateral inhibition; mathematical modeling; spatial pattern.