Steven X. Hou

The JAK/STAT Pathway in Model Organisms: Emerging Roles in Cell Movement

The JAK/STAT pathway was originally identified in mammals. Studies of this pathway in the mouse have revealed that JAK/STAT signaling plays a central role during hematopoeisis and other developmental processes. The role of JAK/STAT signaling in blood appears to be conserved throughout evolution, as it is also required during fly hematopoeisis. Studies in Dictyostelium, Drosophila, and zebrafish have shown that the JAK/STAT pathway is also required in an unusually broad set of developmental decisions, including cell proliferation, cell fate determination, cell migration, planar polarity, convergent extension, and immunity. There is increasing evidence that the versatility of this pathway relies on its cooperation with other signal transduction pathways. In this review, we discuss the components of the JAK/STAT pathway in model organisms and what is known about its requirement in cellular and developmental processes. In particular, we emphasize recent insights into the role that this pathway plays in the control of cell movement.

JAK-STAT Is Restrained by Notch to Control Cell Proliferation of the Drosophila Intestinal Stem Cells

The Drosophila midgut epithelium undergoes continuous regeneration that is sustained by multipotent intestinal stem cells (ISCs) underneath. Notch signaling has dual functions to control ISC behavior: it slows down the ISC proliferation and drives the activated ISCs into different differentiation pathways at a dose‐dependent manner. Here we identified a molecular mechanism to unite these two contradictory functions. We found JAK–STAT signaling controls ISC proliferation and this ability is negatively regulated by Notch at least through a transcriptional control of the JAK–STAT signaling ligand, unpaired (upd). This study provides insight into how stem cells, under steady conditions, balance the processes of proliferation and differentiation to maintain the stable cellular composition of a healthy tissue. J. Cell. Biochem. 109: 992–999, 2010.

Characterization of midgut stem cell- and enteroblast-specific Gal4 lines in drosophila.

The homeostasis of Drosophila midgut is maintained by multipotent intestinal stem cells (ISCs), each of which gives rise to a new ISC and an immature daughter cell, enteroblast (EB), after one asymmetric cell division. In Drosophila, the Gal4‐UAS system is widely used to manipulate gene expression in a tissue‐ or cell‐specific manner, but in Drosophila midgut, there are no ISC‐ or EB‐specific Gal4 lines available. Here we report the generation and characterization of Dl‐Gal4 and Su(H)GBE‐Gal4 lines, which are expressed specifically in the ISCs and EBs separately. Additionally, we demonstrate that Dl‐Gal4 and Su(H)GBE‐Gal4 are expressed in adult midgut progenitors (AMPs) and niche peripheral cells (PCs) separately in larval midgut. These two Gal4 lines will serve as invaluable tools for navigating ISC behaviors. genesis 48:607–611, 2010. Published 2010 Wiley‐Liss, Inc.

Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut

Functional mature cells are continually replenished by stem cells to maintain tissue homoeostasis. In the adult Drosophila posterior midgut, both terminally differentiated enterocyte (EC) and enteroendocrine (EE) cells are generated from an intestinal stem cell (ISC). However, it is not clear how the two differentiated cells are generated from the ISC. In this study, we found that only ECs are generated through the Su(H)GBE+ immature progenitor enteroblasts (EBs), whereas EEs are generated from ISCs through a distinct progenitor pre-EE by a novel lineage-tracing system. EEs can be generated from ISCs in three ways: an ISC becoming an EE, an ISC becoming a new ISC and an EE through asymmetric division, or an ISC becoming two EEs through symmetric division. We further identified that the transcriptional factor Prospero (Pros) regulates ISC commitment to EEs. Our data provide direct evidence that different differentiated cells are generated by different modes of stem cell lineage specification within the same tissues. Summary: The generation of enteroendocrine cells from stem cells in the adult Drosophila midgut occurs via a distinct progenitor stage and involves the transcription factor Prospero.

CKA, a Novel Multidomain Protein, Regulates the JUN N-Terminal Kinase Signal Transduction Pathway in Drosophila

ABSTRACT The Drosophila melanogaster JUN N-terminal kinase (DJNK) and DPP (decapentaplegic) signal transduction pathways coordinately regulate epithelial cell sheet movement during the process of dorsal closure in the embryo. By a genetic screen of mutations affecting dorsal closure in Drosophila, we have now identified a multidomain protein, connector of kinase to AP-1 (cka), that functions in the DJNK pathway and controls the localized expression of dpp in the leading-edge cells. We have also investigated how CKA acts. This unique molecule forms a complex with HEP (DJNKK), BSK (DJNK), DJUN, and DFOS. Complex formation activates BSK kinase, which in turn phosphorylates and activates DJUN and DFOS. These data suggest that CKA represents a novel molecule regulating AP-1 activity by organizing a molecular complex of kinases and transcription factors, thus coordinating the spatial-temporal expression of AP-1-regulated genes.

Competitiveness for the niche and mutual dependence of the germline and somatic stem cells in the Drosophila testis are regulated by the JAK/STAT signaling

In many tissues, two or more types of stem cells share a niche, and how the stem cells coordinate their self‐renewal and differentiation is poorly understood. In the Drosophila testis, germ line stem cells (GSCs) and somatic cyst progenitor cells (CPCs) contact each other and share a niche (the hub). The hub expresses a growth factor unpaired (Upd) that activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in GSCs to regulate the stem cell self‐renewal. Here, we demonstrate that the JAK/STAT signaling also regulates CPCs self‐renewal. We also show that a negative regulator, the suppressor of cytokine signaling 36E (SOCS36E), suppresses JAK/STAT signaling in somatic cells, preventing them from out‐competing the GSCs. Furthermore, through selectively manipulating the JAK/STAT signaling level in either CPCs or GSCs, we demonstrate that the somatic JAK/STAT signaling is essential for self‐renewal and maintenance of both CPCs and GSCs. These data suggest that a single JAK/STAT signal from the niche orchestrate the competitive and dependent co‐existence of GSCs and CPCs in the Drosophila testis niche. J. Cell. Physiol. 223: 500–510, 2010.

Spermatogonial stem cells, infertility and testicular cancer

•  Introduction •  Spermatogonial stem cells ‐  Regulation of SSC maintenance and differentiation ‐  SSC culture, transplantation and plasticity •  SSC in infertility •  SSC in testicular germ cell tumours •  Conclusions

Regulation of intestinal stem cells in mammals and Drosophila.

The digestive systems in mammals and Drosophila are quite different in terms of their complexity and organization, but their biological functions are similar. The Drosophila midgut is a functional equivalent of the mouse small intestine. Adult intestinal stem cells (ISCs) have been identified in both the mouse small intestine and Drosophila midgut. The anatomy and cell renewal in the Drosophila midgut are similar to those in the mouse small intestine: the intestinal epithelium in both systems is a tube composed of epithelial cells with absorptive and secretory functions; the Notch signaling controls absorptive versus secretory fate decisions in the intestinal epithelium; cell renewal in both systems starts from stem cells in the basal cell layer, and the differentiated cells then move toward the lumen. However, it is clear that the stem cells in the two systems are regulated in different ways. In this review, we will compare cell renewal and stem cell regulation in the two systems. J. Cell. Physiol. 222:33–37, 2010.

The adult Drosophila gastric and stomach organs are maintained by a multipotent stem cell pool at the foregut/midgut junction in the cardia (proventriculus).

Stomach cancer is the second most frequent cause of cancer-related death worldwide. Thus, it is important to elucidate the properties of gastric stem cells, including their regulation and transformation. To date, such stem cells have not been identified in Drosophila. Here, using clonal analysis and molecular marker labeling, we identify a multipotent stem-cell pool at the foregut/midgut junction in the cardia (proventriculus). We found that daughter cells migrate upward either to anterior midgut or downward to esophagus and crop. The cardia functions as a gastric valve and the anterior midgut and crop together function as a stomach in Drosophila; therefore, we named the foregut/midgut stem cells as gastric stem cells (GaSC). We further found that JAK-STAT signaling regulates GaSCs’ proliferation, Wingless signaling regulates GaSCs’ self-renewal, and hedgehog signaling regulates GaSCs’ differentiation. The differentiation pattern and genetic control of the Drosophila GaSCs suggest the possible similarity to mouse gastric stem cells. The identification of the multipotent stem cell pool in the gastric gland in Drosophila will facilitate studies of gastric stem cell regulation and transformation in mammal.

Cyclin D-Cdk4 and Cyclin E-Cdk2 Regulate the JAK/STAT Signal Transduction Pathway in Drosophila

The JAK/STAT signal transduction pathway regulates many developmental processes in Drosophila. However, the functional mechanism of this pathway is poorly understood. In this report, we identify the Drosophila cyclin-dependent kinase 4 (Cdk4), which exhibits embryonic mutant phenotypes identical to those in the Hopscotch/JAK kinase and stat92E/STAT mutations. Specific genetic interactions between Cdk4 and hop mutations suggest that Cdk4 functions downstream of the HOP tyrosine kinase. We further show that Cyclin D-Cdk4 (as well as Cyclin E-Cdk2) binds and regulates STAT92E protein stability. STAT92E regulates gene expression for various biological processes, including the endocycle S phase. These data suggest that Cyclin D-Cdk4 and Cyclin E-Cdk2 play more versatile roles in Drosophila development.