In , the sensory organ precursor (SOP or pI cell) divides asymmetrically to give birth to daughter cells, the fates of which are governed by the differential activation of the Notch pathway. Proteolytic activation of Notch induced by ligand is based on the correct polarized sorting and localization of the Notch ligand Delta, the Notch receptor and its trafficking partner Sanpodo (Spdo). Here, we have identified Stratum (Strat), a presumptive guanine nucleotide exchange factor for Rab GTPases, as a regulator of Notch activation. Loss of Strat causes cell fate transformations associated with an accumulation of Notch, Delta and Spdo in the-Golgi network (TGN), and an apical accumulation of Spdo. The mutant phenotype is rescued by the catalytically active as well as the wild-type form of Rab8, suggesting a chaperone function for Strat rather than that of exchange factor. Strat is required to localize Rab8 at the TGN, and phenocopies We propose that Strat and Rab8 act at the exit of the Golgi apparatus to regulate the sorting and the polarized distribution of Notch, Delta and Spdo.

Whole-body health relies on complex inter-organ signalling networks that enable organisms to adapt to environmental perturbations and to changes in tissue homeostasis. The intestine plays a major role as a signalling centre by producing local and systemic signals that are relayed to the body and that maintain intestinal and organismal homeostasis. Consequently, disruption of intestinal homeostasis and signalling are associated with systemic diseases and multi-organ dysfunction. In recent years, the fruit fly Drosophila melanogaster has emerged as a prime model organism to study tissue-intrinsic and systemic signalling networks of the adult intestine due to its genetic tractability and functional conservation with mammals. In this Review, we highlight Drosophila research that has contributed to our understanding of how the adult intestine interacts with its microenvironment and with distant organs. We discuss the implications of these findings for understanding intestinal and whole-body pathophysiology, and how future Drosophila studies might advance our knowledge of the complex interplay between the intestine and the rest of the body in health and disease.

In multiple cell lineages, Delta-Notch signalling regulates cell fate decisions owing to unidirectional signalling between daughter cells. In Drosophila pupal sensory organ lineage, Notch regulates the intra-lineage pIIa/pIIb fate decision at cytokinesis. Notch and Delta that localise apically and basally at the pIIa-pIIb interface are expressed at low levels and their residence time at the plasma membrane is in the order of minutes. How Delta can effectively interact with Notch to trigger signalling from a large plasma membrane area remains poorly understood. Here, we report that the signalling interface possesses a unique apicobasal polarity with Par3/Bazooka localising in the form of nano-clusters at the apical and basal level. Notch is preferentially targeted to the pIIa-pIIb interface, where it co-clusters with Bazooka and its cofactor Sanpodo. Clusters whose assembly relies on Bazooka and Sanpodo activities are also positive for Neuralized, the E3 ligase required for Delta-activity. We propose that the nano-clusters act as snap buttons at the new pIIa-pIIb interface to allow efficient intra-lineage signalling.

Drosophila sensory organ precursors divide asymmetrically to generate pIIa/pIIb cells whose identity relies on the differential activation of Notch at cytokinesis. While Notch is present apically and basally relative to the midbody at the pIIa-pIIb interface, only the basal pool of Notch is reported to contribute to Notch activation in the pIIa cell. Correct intra-lineage signalling requires appropriate apico-basal targeting of Notch, its ligand Delta and its trafficking partner Sanpodo. We previously reported that AP-1 and Stratum regulate the intracellular trafficking of Notch and Sanpodo from the trans-Golgi network to the basolateral membrane. Loss of AP-1 or Stratum caused mild Notch gain-of-function phenotypes. Here, we report that the concomitant loss of AP-1 and Stratum results in a much more penetrant Notch gain-of-function phenotype indicating that AP-1 and Strat control two parallel pathways. While unequal partitioning of cell fate determinants and cell polarity were unaffected, Numb-mediated symmetry breaking is impaired. We further observed increased amounts of signaling competent Notch as well as Delta and Sanpodo at the apical pIIa-pIIb interface and the loss of the basal pool of Notch. We propose that AP-1 and Stratum operate in two parallel pathways to ensure the correct apico-basal localization of Notch controlling where receptor activation takes place.