Polarity determination in the Drosophila eye: a novel role for unpaired and JAK/STAT signaling.
(1/654)
The JAK/STAT signaling pathway is required for many processes including cytokine signaling, hematopoiesis, gliagenesis, and Drosophila segmentation. In this report we present evidence demonstrating that the JAK/STAT pathway is also central to the establishment of planar polarity during Drosophila eye development. We show that a localized source of the pathway ligand, Unpaired, is present at the midline of the developing eye, which is capable of activating the JAK/STAT pathway over long distances. A gradient of JAK/STAT activity across the DV axis of the eye regulates ommatidial polarity via an unidentified second signal. Additionally, localized Unpaired influences the position of the equator via repression of mirror. (+info)
The phosphorylated C-terminus of cAR1 plays a role in cell-type-specific gene expression and STATa tyrosine phosphorylation.
(2/654)
cAMP receptors mediate some signaling pathways via coupled heterotrimeric G proteins, while others are G-protein-independent. This latter class includes the activation of the transcription factors GBF and STATa. Within the cellular mounds formed by aggregation of Dictyostelium, micromolar levels of cAMP activate GBF function, thereby inducing the transcription of postaggregative genes and initiating multicellular differentiation. Activation of STATa, a regulator of culmination and ecmB expression, results from cAMP receptor-dependent tyrosine phosphorylation and nuclear localization, also in mound-stage cells. During mound development, the cAMP receptor cAR1 is in a low-affinity state and is phosphorylated on multiple serine residues in its C-terminus. This paper addresses possible roles of cAMP receptor phosphorylation in the cAMP-mediated stimulation of GBF activity, STATa tyrosine phosphorylation, and cell-type-specific gene expression. To accomplish this, we have expressed cAR1 mutants in a strain in which the endogenous cAMP receptors that mediate postaggregative gene expression in vivo are deleted. We then examined the ability of these cells to undergo morphogenesis and induce postaggregative and cell-type-specific gene expression and STATa tyrosine phosphorylation. Analysis of cAR1 mutants in which the C-terminal tail is deleted or the ligand-mediated phosphorylation sites are mutated suggests that the cAR1 C-terminus is not essential for GBF-mediated postaggregative gene expression or STATa tyrosine phosphorylation, but may play a role in regulating cell-type-specific gene expression and morphogenesis. A mutant receptor, in which the C-terminal tail is constitutively phosphorylated, exhibits constitutive activation of STATa tyrosine phosphorylation in pulsed cells in suspension and a significantly impaired ability to induce cell-type-specific gene expression. The constitutively phosphorylated receptor also exerts a partial dominant negative effect on multicellular development when expressed in wild-type cells. These findings suggest that the phosphorylated C-terminus of cAR1 may be involved in regulating aspects of receptor-mediated processes, is not essential for GBF function, and may play a role in mediating subsequent development. (+info)
Tyrosine phosphorylation-independent nuclear translocation of a dictyostelium STAT in response to DIF signaling.
(3/654)
We describe a Dictyostelium STAT, Dd-STATc, which regulates the speed of early development and the timing of terminal differentiation. Dd-STATc also functions as a repressor, which directs graded expression of the ecmA gene in different prestalk cell populations. Developing Dictyostelium cells produce a chlorinated hexaphenone, DIF, which directs prestalk cell differentiation. Dd-STATc is tyrosine phosphorylated, dimerizes, and translocates to the nucleus when cells are exposed to DIF. Surprisingly, however, SH2 domain-phosphotyrosine interaction is not necessary for the DIF-induced nuclear translocation of Dd-STATc. In this respect, Dd-STATc activation resembles several recently described, noncanonical mammalian STAT signaling processes. We show instead that DIF mediates nuclear translocation via sequences located in the divergent, N-terminal half of the Dd-STATc molecule. (+info)
Adenylyl cyclase A expression is tip-specific in Dictyostelium slugs and directs StatA nuclear translocation and CudA gene expression.
(4/654)
cAMP oscillations, generated by adenylyl cyclase A (ACA), coordinate cell aggregation in Dictyostelium and have also been implicated in organizer function during multicellular development. We used a gene fusion of the ACA promoter with a labile lacZ derivative to study the expression pattern of ACA. During aggregation, most cells expressed ACA, but thereafter expression was lost in all cells except those of the anterior tip. Before aggregation, ACA transcription was strongly upregulated by nanomolar cAMP pulses. Postaggregative transcription was sustained by nanomolar cAMP pulses, but downregulated by a continuous micromolar cAMP stimulus and by the stalk-cell-inducing factor DIF. Earlier work showed that the transcription factor StatA displays tip-specific nuclear translocation and directs tip-specific expression of the nuclear protein CudA, which is essential for culmination. Both StatA and CudA were present in nuclei throughout the entire slug in an aca null mutant that expresses ACA from the constitutive actin15 promoter. This suggests that the tip-specific expression of ACA directs tip-specific nuclear translocation of StatA and tip-specific expression of CudA. (+info)
A Drosophila PIAS homologue negatively regulates stat92E.
(5/654)
Transcriptional activation by, and therefore the physiologic impact of, activated tyrosine-phosphorylated STATs (signal transducers and activators of transcription) may be negatively regulated by proteins termed PIAS (protein inhibitors of activated stats), as shown by previous experiments with mammalian cells in culture. Here, by using the genetic modifications in Drosophila, we demonstrate the in vivo functional interaction of the Drosophila homologues stat92E and a Drosophila PIAS gene (dpias). To this end we use a LOF allele and conditionally overexpressed dpias in JAK-STAT pathway mutant backgrounds. We conclude that the correct dpias/stat92E ratio is crucial for blood cell and eye development. (+info)
Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue.
(6/654)
Stem cells generate many differentiated, short-lived cell types, such as blood, skin, and sperm, throughout adult life. Stem cells maintain a long-term capacity to divide, producing daughter cells that either self-renew or initiate differentiation. Although the surrounding microenvironment or "niche" influences stem cell fate decisions, few signals that emanate from the niche to specify stem cell self-renewal have been identified. Here we demonstrate that the apical hub cells in the Drosophila testis act as a cellular niche that supports stem cell self-renewal. Hub cells express the ligand Unpaired (Upd), which activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in adjacent germ cells to specify self-renewal and continual maintenance of the germ line stem cell population. (+info)
Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling.
(7/654)
Stem cells, which regenerate tissue by producing differentiating cells, also produce cells that renew the stem cell population. Signals from regulatory microenvironments (niches) are thought to cause stem cells to retain self-renewing potential. However, the molecular characterization of niches remains an important goal. In Drosophila testes, germ line and somatic stem cells attach to a cluster of support cells called the hub. The hub specifically expresses Unpaired, a ligand activating the JAK-STAT (Janus kinase-signal transducer and activator of transcription) signaling cascade. Without JAK-STAT signaling, germ line stem cells differentiate but do not self-renew. Conversely, ectopic JAK-STAT signaling greatly expands both stem cell populations. We conclude that the support cells of the hub signal to adjacent stem cells by activation of the JAK-STAT pathway, thereby defining a niche for stem cell self-renewal. (+info)
Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila.
(8/654)
The JAK/STAT signaling pathway, renowned for its effects on cell proliferation and survival, is constitutively active in various human cancers, including ovarian. We have found that JAK and STAT are required to convert the border cells in the Drosophila ovary from stationary, epithelial cells to migratory, invasive cells. The ligand for this pathway, Unpaired (UPD), is expressed by two central cells within the migratory cell cluster. Mutations in upd or jak cause defects in migration and a reduction in the number of cells recruited to the cluster. Ectopic expression of either UPD or JAK is sufficient to induce extra epithelial cells to migrate. Thus, a localized signal activates the JAK/STAT pathway in neighboring epithelial cells, causing them to become invasive. (+info)