The Drosophila Importin-a3 Is Required for Nuclear Import of Notch In Vivo and It Displays Synergistic Effects with Notch Receptor on Cell Proliferation

The Notch signaling pathway controls diverse cell-fate specification events throughout development. The versatility of this pathway to influence different aspects of development comes from its multiple levels of regulation. Upon ligand-induced Notch activation, the Notch intracellular domain (Notch-ICD) is released from the membrane and translocates to the nucleus, where it transduces Notch signals by regulating the transcription of downstream target genes. But the exact mechanism of translocation of Notch-ICD into the nucleus is not clear. Here, we implicate Importin-a3 (also known as karyopherin-a3) in the nuclear translocation of Notch-ICD in Drosophila. Our present analyses reveal that Importin-a3 can directly bind to Notch-ICD and loss of Importin-a3 function results in cytoplasmic accumulation of the Notch receptor. Using MARCM (Mosaic Analysis with a Repressible Cell Marker) technique, we demonstrate that Importin-a3 is required for nuclear localization of Notch-ICD. These results reveal that the nuclear transport of Notch-ICD is mediated by the canonical Importin-a3/Importin-b transport pathway. In addition, co-expression of both Notch-ICD and Importin-a3 displays synergistic effects on cell proliferation. Taken together, our results suggest that Importin-a3 mediated nuclear import of Notch-ICD may play important role in regulation of Notch signaling