title: Numb inhibits the recycling of Sanpodo in Drosophila sensory organ precursor.
abstract: In metazoans, unequal partitioning of the cell-fate determinant Numb underlies the generation of distinct cell fates following asymmetric cell division [1-5]. In Drosophila, during asymmetric division of the sensory organ precursor (SOP) cell, Numb is unequally inherited by the pIIb daughter cell, where it antagonizes Notch [1, 6-8]. Numb inhibits Notch partly through inhibiting the plasma membrane localization of Sanpodo (Spdo), a transmembrane protein required for Notch signaling during asymmetric cell division [9, 10]. Numb, by binding to Spdo and α-Adaptin, was proposed to mediate Spdo endocytosis alone or bound to Notch in the pIIb cell, thereby preventing Notch activation [11-16]. However, in addition to endocytosis, Numb also controls the postendocytic trafficking and degradation of Notch in mammals [17, 18] and negatively regulates basolateral recycling in C. elegans [19, 20]. Thus, whether Numb promotes the endocytosis of Spdo is a question that requires experimental demonstration and is therefore investigated in this article. Based on internalization assays, we show that Spdo endocytosis is restricted to cells in interphase and requires AP-2 activity. Surprisingly, the bulk endocytosis of Spdo occurs properly in numb mutant SOP, indicating that Numb does not regulate the steady-state localization of Spdo via Spdo internalization. We report that Numb genetically and physically interacts with AP-1, a complex regulating the basolateral recycling of Spdo [21]. In numb mutant organs, Spdo is efficiently internalized and recycled back to the plasma membrane. We propose that Numb acts in concert with AP-1 to control the endocytic recycling of Spdo to regulate binary-fate decisions.
authors.affiliation: CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Université de Rennes 1, 35043 Rennes, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Cotton
authors.forename: Najate
authors.initials: N
authors.lastname: Benhra
authors.forename: Roland
authors.initials: R
authors.lastname: Le Borgne
mesh_terms: D033965:Adaptor Protein Complex alpha Subunits / Q000378:metabolism; D000818:Animals; D060049:Asymmetric Cell Division / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D047468:Immunoprecipitation; D007605:Juvenile Hormones / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D058953:Neural Stem Cells / Q000502:physiology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors; D011984:Sensory Receptor Cells / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000378:metabolism
chemical_list: D033965:Adaptor Protein Complex alpha Subunits; D029721:Drosophila Proteins; D007605:Juvenile Hormones; D008840:Microfilament Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C493674:TfAP-2 protein, Drosophila; D018808:Transcription Factor AP-1; D050656:Transcription Factor AP-2; C060606:numb protein, Drosophila; C112833:spdo protein, Drosophila