Decoding ‘Wntch’: the intertwined Wnt and Notch pathways in development and disease

Abstract Multicellularity emerges from the ability of cells to undergo functional differentiation. One of the key mechanisms that enables this coordination is cellular signalling—a series of molecular interactions within or between cells that induce changes in cell behaviour or gene expression. As the body plan of multicellular organisms becomes more complex, so does the sophistication of their signalling systems. The Wnt and Notch pathways are central to regulating cell fate, tissue development and maintenance in all studied metazoa. Affecting overlapping biological processes, often within short developmental time windows, these molecular systems appear to be functionally interconnected, leading to the proposal of a ‘Wntch’ signalling concept. This concept implies that Wnt and Notch modules do not operate as isolated linear pathways but form a coherent network that integrates signals to ensure precise control of developmental and physiological outcomes. In this review, we synthesize both past and recent insights into the direct crosstalk of Wnt and Notch signalling molecules, examine crosstalk within the context of recently developed assays such as single-cell RNA sequencing and proximity labelling, and discuss the broader implications of this interplay in development and disease.