Molecular separation of two signaling pathways for the receptor, Notch.
Notch is required for many aspects of cell fate specification and morphogenesis during development, including neurogenesis and axon guidance. We here provide genetic and biochemical evidence that Notch directs axon growth and guidance in Drosophila via a "non-canonical", i.e. non-Su(H)-mediated, signaling pathway, characterized by association with the adaptor protein, Disabled, and Trio, an accessory factor of the Abl tyrosine kinase. We find that forms of Notch lacking the binding sites for its canonical effector, Su(H), are nearly inactive for the cell fate function of the receptor, but largely or fully active in axon patterning. Conversely, deletion from Notch of the binding site for Disabled impairs its action in axon patterning without disturbing cell fate control. Finally, we show by co-immunoprecipitation that Notch protein is physically associated in vivo with both Disabled and Trio. Together, these data provide evidence for an alternate Notch signaling pathway that mediates a postmitotic, morphogenetic function of the receptor.
Axon Guidance and Neural Connectivity Unit, Basic Neuroscience Program, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bldg. 37, Rm. 1016, 37 Convent Drive, Bethesda, MD 20892, USA.
Maude
M
Le Gall
Cordell
C
De Mattei
Edward
E
Giniger
D000483:Alleles; D000818:Animals; D001369:Axons / Q000502:physiology; D001665:Binding Sites; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004625:Embryo, Nonmammalian; D004926:Escherichia coli / Q000235:genetics; D005982:Glutathione Transferase / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006639:Histidine / Q000378:metabolism; D007150:Immunohistochemistry; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051880:Receptors, Notch / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D019076:Transgenes
D029721:Drosophila Proteins; D020662:Guanine Nucleotide Exchange Factors; D019476:Insect Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C080216:dab protein, Drosophila; D006639:Histidine; D005982:Glutathione Transferase; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C490974:trio protein, Drosophila