In mammals, the JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is activated in response to cytokines and growth factors to control blood cell development, proliferation and cell determination. In Drosophila, a conserved JAK/STAT signaling pathway controls segmentation in embryos, as well as blood cell development and other processes in larvae and adults. During embryogenesis, transduction of the Unpaired [Upd; also known as Outstretched (Os)] ligand through the JAK/STAT pathway requires Domeless, a putative membrane protein with distant homology to vertebrate type I cytokine receptors. We have isolated domeless(dome) in a screen to identify genes essential in epithelial morphogenesis during oogenesis. The level of dome activity is critical for proper border cell migration and is controlled in part through a negative feedback loop. In addition to its essential role in border cells, we show that dome is required in the germarium for the polarization of follicle cells during encapsulation of germline cells. In this process,dome controls the expression of the apical determinant Crumbs. In contrast to the ligand Upd, whose expression is limited to a pair of polar cells at both ends of the egg chamber, dome is expressed in all germline and follicle cells. However, the Dome protein is specifically localized at apicolateral membranes and undergoes ligand-dependent internalization in the follicle cells. dome mutations interact genetically with JAK/STAT pathway genes in border cell migration and abolish the nuclear translocation of Stat92E in vivo. We also show that domefunctions downstream of upd and that both the extracellular and intracellular domains of Dome are required for JAK/STAT signaling. Altogether,our data indicate that Dome is an essential receptor molecule for Upd and JAK/STAT signaling during oogenesis.

Many cytokines, including interferons, interleukins, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF) and growth factors, are major activators of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signalling pathway in mammals. JAK/STAT activity has been associated with several diseases, including cancer (leukaemia), myocardial hypertrophy and asthma, and knockout studies indicate a central role for JAK/STAT signalling in haematopoiesis, immune function, cell growth, differentiation and development (Agaisse and Perrimon,

The basement membrane (BM), a specialized sheet of the extracellular matrix contacting the basal side of epithelial tissues, plays an important role in the control of the polarized structure of epithelial cells. However, little is known about how BM proteins themselves achieve a polarized distribution. Here, we identify phosphatidylinositol 4,5-bisphosphate (PIP2) as a critical regulator of the polarized secretion of BM proteins. A decrease of PIP2 levels, in particular through mutations in Phosphatidylinositol synthase (Pis) and other members of the phosphoinositide pathway, leads to the aberrant accumulation of BM components at the apical side of the cell without primarily affecting the distribution of apical and basolateral polarity proteins. In addition, PIP2 controls the apical and lateral localization of Crag (Calmodulin-binding protein related to a Rab3 GDP/GTP exchange protein), a factor specifically required to prevent aberrant apical secretion of BM. We propose that PIP2, through the control of Crag's subcellular localization, restricts the secretion of BM proteins to the basal side.cell polarity | PTEN | PIK | Drosophila | oogenesis E pithelial cells are characterized by their polarized architecture, which enables them to exert their varied functions in embryonic and adult organisms. Epithelia exhibit a profound apical-basal polarity that is manifested in the cytoplasmic and surface organization of individual cells (1-3). Loss of apicalbasal cell polarity is often associated with carcinoma progression and tumor metastasis (4, 5). The establishment and maintenance of cell polarity relies on the transport of newly synthesized and recycled proteins to their correct destinations (6, 7). The lipid composition of the transport vesicles and of the plasma membrane is crucial for the establishment and maintenance of cell polarity (6-9). In particular, in 3D in vitro culture of Madin-Darby canine kidney (MDCK) cells, phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3), two phosphoinositides (PtdIns) have been shown to play critical roles in polarized vesicle trafficking by mediating the recruitment of proteins to these different domains (10, 11).To set up a correct cell polarity, membrane asymmetry needs to be established. In cell culture, and likely during development of many tissues in multicellular organisms, this process is achieved by two external cues: one provided by the adjacent cells via cadherin-dependent adhesion and the other by interaction with the basement membrane (BM), a specialized sheet of the ECM secreted basally by the epithelial cells (12, 13). The main components of the BM are secreted glycoproteins, such as collagen IV (Coll IV), laminin, and the heparan sulfate proteoglycan perlecan (Pcan) (14), which interact with different membrane receptors, including integrin and dystroglycan (14,15). Previous studies in model organisms and 3D culture models have shown that BM secreted by the epithelial cells at their basal side plays a role as an initial ...