Bimodal Transcription Regulates Non-Canonical Signaling of Notch 1

Abstract

Notch is a critical determinant of tissue organisation in metazoan development. The activation of Notch signaling is based on ligand-receptor interaction, consequentially the activated intracellular Notch domain is chaperoned into the nuclear compartment where it acts as a transcriptional activator for Notch target genes, leading to a biological outcome that may or may not be predictable. Upon activation, downstream signals contribute to resolution of dichotomies such as proliferation/differentiation or sub-lineage differentiation outcome. Idiosyncratic outcomes are common, leading experimentalists to describe a ‘non-canonical’ pathway for Notch signaling. It has been proposed that inappropriate activation of Notch could drive abnormal biological response and pathological disruption. Herein, we sought evidence for uncharacteristic activation of Notch signaling and a possible biological outcome. We provide an alternative interpretation of the Notch cascade and have identified an unrecognized intragenic enhancer responsible for independent transcription of the 3ʹ aspect of the gene that encodes a truncated intracellular domain (NICDtr). This novel form of Notch 1 was demonstrated to regulate differentiation fate choice in neural precursors. Moreover, we propose a novel understanding of non-canonical activation and unforeseen interplay with the nonsense-mediated decay (NMD) degradation complex.