Review Article

Nybakken K, Perrimon N. Hedgehog signal transduction: recent findings. Curr Opin Genet Dev. 2002;12 (5) :503-11. Abstract

The Hedgehog (Hh) family of signaling molecules are key agents in patterning numerous types of tissues. Mutations in Hh and its downstream signaling molecules are also associated with numerous oncogenic and disease states. Consequently, understanding the mechanisms by which Hh signals are transduced is important for understanding both development and disease. Recent studies have clarified several aspects of Hh signal transduction. Several new Sonic Hedgehog binding partners have been identified. Cholesterol and palmitic acid modifications of Hh and Sonic hedgehog have been examined in greater detail. Characterization of the trafficking patterns of the Patched and Smoothened proteins has demonstrated that these two proteins function very differently from the previously established models. The Fused kinase has been demonstrated to phosphorylate the kinesin-like protein Costal2 and the sites identified, while Cubitus interruptus has been shown to be phosphorylated in a hierarchical manner by three different kinases. Finally, the interactions, both genetic and physical, between Fused, Costal2, Cubitus interruptus, and Suppressor of Fused have been further elucidated.

Nybakken K, Perrimon N. Heparan sulfate proteoglycan modulation of developmental signaling in Drosophila. Biochim Biophys Acta. 2002;1573 (3) :280-91. Abstract

Heparan sulphate proteoglycans (HSPG's) are cell surface proteins to which long, unbranched chains of modified sugars called heparan sulphate glycosaminoglycans have been covalently attached. Cell culture studies have demonstrated that HSPG's are required for optimal signal transduction by many secreted cell signaling molecules. Now, genetic studies in both Drosophila and vertebrates have illustrated that HSPG's play important roles in signal transduction in vivo and have also begun to reveal new roles for HSPG's in signaling events. In particular, HSPG's have been shown to be important in ligand sequestration of wingless, for the transport of the Hedgehog ligand, and for modulation of the Dpp morphogenetic gradient.

Hou SX, Zheng Z, Chen X, Perrimon N. The Jak/STAT pathway in model organisms: emerging roles in cell movement. Dev Cell. 2002;3 (6) :765-78. Abstract

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.

2002_Dev Cell_Hou.pdf
Schock F, Perrimon N. Molecular mechanisms of epithelial morphogenesis. Annu Rev Cell Dev Biol. 2002;18 :463-93. Abstract

Epithelial morphogenesis comprises the various processes by which epithelia contribute to organ formation and body shape. These complex and diverse events play a central role in animal development and regeneration. Recently, the characterization of some of the molecular mechanisms involved in epithelial morphogenesis has provided an abundance of new information on the role and regulation of the cytoskeleton, cell-cell adhesion, and cell-matrix adhesion in these processes. In this review, we discuss our current understanding of the molecular mechanisms driving cell shape changes, cell intercalation, fusion of epithelia, ingression, egression, and cell migration. Our discussion is mostly focused on results from Drosophila and mammalian tissue culture but also draws on the insights gained from other organisms.

2002_Annu Rev Cell Dev_Schock.pdf
Moon RT, Bowerman B, Boutros M, Perrimon N. The promise and perils of Wnt signaling through beta-catenin. Science. 2002;296 (5573) :1644-6. Abstract

Wnt pathways are involved in the control of gene expression, cell behavior, cell adhesion, and cell polarity. In addition, they often operate in combination with other signaling pathways. The Wnt/beta-catenin pathway is the best studied of the Wnt pathways and is highly conserved through evolution. In this pathway, Wnt signaling inhibits the degradation of beta-catenin, which can regulate transcription of a number of genes. Some of the genes regulated are those associated with cancer and other diseases (for example, colorectal cancer and melanomas). As a result, components of the Wnt/beta-catenin pathway are promising targets in the search for therapeutic agents. Information about Wnt pathways is available both in canonical terms and at the species level. In addition to the canonical Wnt/beta-catenin pathway, information is now available for Drosophila, Caenorhabditis elegans, and Xenopus. The STKE Connections Maps for these pathways provide an important tool in accessing this large body of complex information.

Schober M, Perrimon N. Unconventional ways to travel. Nat Cell Biol. 2002;4 (9) :E211-2. 2002_Nat Cell Bio_Schober.pdf
Perrimon N, Bernfield M. Cellular functions of proteoglycans--an overview. Semin Cell Dev Biol. 2001;12 (2) :65-7. 2001_Sem Cell Dev Bio_Perrimon.pdf
Vincent S, Perkins LA, Perrimon N. Doublesex surprises. Cell. 2001;106 (4) :399-402. 2001_Cell_Vincent.pdf
Vincent S, Perrimon N. Fishing for morphogens. Nature. 2001;411 (6837) :533, 535-6. 2001_Nat_Vincent.pdf
Selva EM, Perrimon N. Role of heparan sulfate proteoglycans in cell signaling and cancer. Adv Cancer Res. 2001;83 :67-80. 2001_Adv Cancer Res_Selva.pdf
Bellaiche Y, The I, Perrimon N. [Role des proteoglycanes dans la distribution du facteur secrete Hedgehog] (French). Medecine Sciences . 2000;2 :250-252.
Boutros M, Perrimon N. Drosophila genome takes flight. Nat Cell Biol. 2000;2 (4) :E53-4. Abstract

In the March 24 issue of Science, a flurry of papers report on the impending completion of the Drosophila melanogaster genome sequence. This historic achievement is the result of a unique collaboration between the Berkeley Drosophila Genome Project (BDGP), led by Gerry Rubin, and the genomics company Celera, headed by Craig Venter. With its genome almost completely sequenced ahead of schedule, Drosophila is another important model organism to enter the postgenomic age, and represents the largest genome sequenced to date.

2000_Nat Cell Bio_Boutros.pdf
Baeg GH, Perrimon N. Functional binding of secreted molecules to heparan sulfate proteoglycans in Drosophila. Curr Opin Cell Biol. 2000;12 (5) :575-80. Abstract

Heparan sulfate proteoglycans (HSPGs) are associated with the cell surface and covalently linked to a small number of long unbranched chains of repeating disaccharides. Numerous biochemical studies of these extracellular matrix molecules have implicated them in a variety of biological phenomena, in particular cell-cell interactions. Recent genetic studies in Drosophila have begun to clarify the function of HSPGs in vivo and recent findings have implicated HSPGs in Wnt, Hedgehog, fibroblast growth factor and transforming growth factor-beta signaling pathways during development.

2000_Curr Op Cell Bio_Baeg.pdf
The I, Perrimon N. Morphogen diffusion: the case of the wingless protein. Nat Cell Biol. 2000;2 (5) :E79-82. 2000_Nat Cell Bio_The.pdf
Lin X, Perrimon N. Role of heparan sulfate proteoglycans in cell-cell signaling in Drosophila. Matrix Biol. 2000;19 (4) :303-7. Abstract

Heparan sulfate proteoglycans (HSPGs) are abundant molecules associated with the cell surface and extracellular matrix, and consist of a protein core to which heparan sulfate (HS) glycosaminoglycan (GAG) chains are attached. Although these molecules have been the focus of intense biochemical studies in vitro, their biological functions in vivo were unclear until recently. We have undertaken an in vivo functional study of HSPGs in Drosophila. Our studies, as well as others, demonstrate the critical roles of HSPGs in several major signaling pathways, including ibroblast growth factor (FGF), Wnt, Hedgehog (Hh) and TGF-beta. Our results also suggest that specific HS GAG chain modifications, as well as specific HSPG protein cores, are involved in specific signaling pathways.

2000_Matrix Bio_Lin.pdf
Zeidler MP, Bach EA, Perrimon N. The roles of the Drosophila JAK/STAT pathway. Oncogene. 2000;19 (21) :2598-606. Abstract

The JAK/STAT signal transduction pathway has been conserved throughout evolution such that true structural and functional homologues of components originally identified in vertebrate systems are also present in the model genetic system Drosophila melanogaster. In addition to roles during larval hematopoiesis reminiscent of the requirement for this pathway in mammalian systems, the JAK/STAT pathway in Drosophila is also involved in a number of other developmental events. Recent data has demonstrated further roles for the JAK/STAT pathway in the establishment of sexual identity via the early embryonic expression of Sex lethal, the segmentation of the embryo via the control of pair rule genes including even skipped and the establishment of polarity within the adult compound eye via a mechanism that includes the four jointed gene. Use of the powerful genetics in the model organism Drosophila may identify new components of the JAK/STAT pathway, define new roles for this pathway, and provide insights into the function of this signal transduction system. Here we review the roles of STAT and its associated signaling pathway during both embryonic and adult stages of Drosophila development and discuss future prospects for the identification and characterization of novel pathway components and targets. Oncogene (2000).

Zeidler MP, Perrimon N. Sex determination: co-opted signals determine gender. Curr Biol. 2000;10 (18) :R682-4. Abstract

The Drosophila JAK-STAT pathway and its ligand Unpaired are required for a wide range of developmental processes. Recent results have identified Unpaired as an activator of sex-lethal and revealed a new role for the JAK-STAT pathway in sex determination.

2000_Curr Bio_Zeidler.pdf
Noselli S, Perrimon N. Signal transduction. Are there close encounters between signaling pathways?. Science. 2000;290 (5489) :68-9. Abstract

Do different signaling pathways inside the same cell talk to each other? Evidence suggests that in the worm and fly, signaling pathways exist as separate linear cassettes, whereas in mammalian cells there does appear to be cross talk between signaling pathways. However, as Noselli and Perrimon argue in their Perspective, most of the evidence in mammalian cells comes from tumor cells and overexpression assays. They suggest that true cross talk may not actually exist in mammalian cells under normal circumstances.   

Perrimon N, Bernfield M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature. 2000;404 (6779) :725-8. Abstract

Heparan sulphate proteoglycans are abundant cell-surface molecules that consist of a protein core to which heparan sulphate glycosaminoglycan chains are attached. The functions of these molecules have remained mostly underappreciated by developmental biologists; however, the actions of important signalling molecules, for example Wnt and Hedgehog, depend on them. To understand both the mechanisms by which ligands involved in development interact with their receptors and how morphogens pattern tissues, biologists need to consider the functions of heparan sulphate proteoglycans in signalling and developmental patterning.