AP-1 Controls the Trafficking of Notch and Sanpodo toward E-Cadherin Junctions in Sensory Organ Precursors

Abstract

In Drosophila melanogaster, external sensory organs develop from a single sensory organ precursor (SOP). The SOP divides asymmetrically to generate daughter cells, whose fates are governed by differential Notch activation. Here we show that the clathrin adaptor AP-1 complex, localized at the trans Golgi network and in recycling endosomes, acts as a negative regulator of Notch signaling. Inactivation of AP-1 causes ligand-dependent activation of Notch, leading to a fate transformation within sensory organs. Loss of AP-1 affects neither cell polarity nor the unequal segregation of the cell fate determinants Numb and Neuralized. Instead, it causes apical accumulation of the Notch activator Sanpodo and stabilization of both Sanpodo and Notch at the interface between SOP daughter cells, where DE-cadherin is localized. Endocytosis-recycling assays reveal that AP-1 acts in recycling endosomes to prevent internalized Spdo from recycling toward adherens junctions. Because AP-1 does not prevent endocytosis and recycling of the Notch ligand Delta, our data indicate that the DE-cadherin junctional domain may act as a launching pad through which endocytosed Notch ligand is trafficked for signaling.

Regulation of centrosome movements by Numb and the Collapsin Response Mediator Protein during Drosophila sensory progenitor asymmetric division

“…5A-CЈ). Although the Rab11 function during pI cell division has not been directly tested owing to its role in cytokinesis, several findings indicate that the Delta ligand transits the Rab11 endosome to reach the pI daughter cell interface to promote Notch signalling and the specification of the pIIa cell fate (Benhra et al, 2011;Benhra et al, 2010;Emery et al, 2005;Jafar-Nejad et al, 2005). Accordingly, we observed that fluorescently labelled internalized 2663 RESEARCH ARTICLE Centrosome movement regulation Delta antibodies can be found localized around the anterior pI centrosome during cytokinesis (Fig.…”

“…Neur promotes Delta endocytosis in the anterior pI daughter cell (Benhra et al, 2010;Le Borgne and Schweisguth, 2003b). The Delta recycling to the apical pIIa/pIIb interface is then accomplished through the Rab11 positive endosomes (Benhra et al, 2011;Benhra et al, 2010;Emery et al, 2005). Among other activities, Delta recycling requires the exocyst complex and the formation of apical actin-rich (ARS) structure at the level of the apical midbody, which forms upon pI cytokinesis (Jafar-Nejad et al, 2005;Langevin et al, 2005b;Rajan et al, 2009).…”

“…Yet, in telophase, a 'telophase rescue' mechanism promotes their asymmetric localization in the absence of Baz or Pins (Raps -FlyBase) activity (Bellaïche et al, 2001b). During cytokinesis and in the anterior daughter cell, Numb and α-Adaptin (Ada) promote the endocytosis of the Notch receptor, via Sanpodo (Spdo)-dependent and -independent mechanisms, thereby reducing the plasma membrane accumulation of Notch at the pI daughter cell interface (Babaoglan et al, 2009;Benhra et al, 2011;Couturier et al, 2012;Hutterer and Knoblich, 2005;O'Connor-Giles and Skeath, 2003;Roegiers et al, 2005;Santolini et al, 2000;Tong et al, 2010). In parallel, Delta is activated in the anterior pI daughter by a Neur-dependent mechanism.…”

Numb regulates vesicular docking for homotypic fusion of early endosomes via membrane recruitment of Mon1b

“…Numb carries out these functions via regulating endocytic trafficking of several key molecules, such as Notch, sanpodo, cadherins and integrins [4,7,9,14,17,18,23,24,26,51,52]. Although in all these contexts Numb functions as an endocytic adaptor protein, the exact role of Numb in endocytic trafficking remains an open question.…”

Interaction of Notch Signaling Modulator Numb with α-Adaptin Regulates Endocytosis of Notch Pathway Components and Cell Fate Determination of Neural Stem Cells

“…These observations strongly suggest that N endocytosis was impaired in ␣-ada or numb mutant IPs and NBs. More direct proof of altered N endocytosis in ␣-ada or numb mutant IPs may come from a live antibody uptake assay, as done in other tissues (34,37,48,49). However, the thickness of whole brain tissues has so far posed a technical challenge for this approach.…”