Review Article

Shulman JM, Perrimon N, Axelrod JD. Frizzled signaling and the developmental control of cell polarity. Trends Genet. 1998;14 (11) :452-8. Abstract

Within the last three years, Frizzled receptors have risen from obscurity to celebrity status owing to their functional identification as receptors for the ubiquitous family of secreted WNT signaling factors. However, the founding member of the Frizzled family, Drosophila Frizzled (FZ), was cloned almost a decade ago because of its role in regulating cell polarity within the plane of an epithelium. In this review, we consider the role of FZ in this intriguing context. We discuss recent progress towards elucidating mechanisms for the intracellular specification of planar polarity, and further review evidence for models of global polarity regulation at the tissue level. The data suggest that a genetic 'cassette', encoding a set of core signaling components, could pattern hair, bristle and ommatidial planar polarity in Drosophila, and that additional tissue-specific factors might explain the diversity of signal responses. Recently described examples from the nematode and frog suggest that the developmental control of cell polarity by FZ receptors might represent a functionally conserved signaling mechanism.

1998_Trends Genet_Shulman.pdf
Perrimon N, Nusse R. Highlights of the 1998 Wnt meeting, Cambridge, MA, January 9-11. Biochim Biophys Acta. 1998;1377 (3) :R45-9. 1998_BBA_Perrimon.pdf
Mathey-Prevot B, Perrimon N. Mammalian and Drosophila blood: JAK of all trades?. Cell. 1998;92 (6) :697-700. 1998_Cell_Prevot.pdf
Perrimon N, Duffy JB. Sending all the right signals. Nature. 1998;396 (6706) :18-9. 1998_Nat_Perrimon.pdf
Duffy JB, Perrimon N. Recent advances in understanding signal transduction pathways in worms and flies. Curr Opin Cell Biol. 1996;8 (2) :231-8. Abstract

One major challenge in the fields of signal transduction and pattern formation is to understand how multiple signals are integrated to determine cell fates. Two developmental systems, vulval development in Caenorhabditis elegans and axis formation during Drosophila melanogaster oogenesis, require the epidermal growth factor receptor tyrosine kinase and the NOTCH signaling pathways to specify cell fates. Current work in both systems has provided new opportunities to investigate the potential for the cross-talk between these different signaling pathways.

1996_Curr Op Cell Bio_Duffy.pdf
Perrimon N. Serpentine proteins slither into the wingless and hedgehog fields. Cell. 1996;86 (4) :513-6. 1996_Cell_Perrimon.pdf
Perrimon N, Lu X, Hou XS, Hsu JC, Melnick MB, Chou TB, et al. Dissection of the Torso signal transduction pathway in Drosophila. Mol Reprod Dev. 1995;42 (4) :515-22. Abstract

Cell fate choice at the anterior and posterior embryonic termini of the Drosophila embryo requires the activation of a signal transduction pathway regulated by the receptor tyrosine kinase Torso. When Torso, which is uniformly distributed in the egg cell membrane, becomes activated locally at the termini, it triggers a phosphorylation cascade that culminates with localized expression of the transcription factors, tailless and huckebein. Expression of tailless and huckebein in turn determines terminal cell fates. Several genes have been characterized which encode proteins that are involved in Torso signaling: the adaptor protein Drk, the GTP-binding protein Ras1, the guanine nucleotide exchange factor Son of sevenless, and the kinases D-Raf and D-Mek. Genetic and molecular evidence supports a model in which these proteins lie in the same biochemical pathway. When activated by its ligand the membrane-bound receptor tyrosine kinase Torso initiates a signal transduction pathway mediated by Drk, Sos, and Ras1, which in turn activates a phosphorylation cascade mediated by the kinases D-Raf and D-Mek, which ultimately control the localized expression of the transcription factors tailless and huckebein. Recently, we found that D-Raf can be partially activated by Torso in the absence of Ras1, a finding supported by the phenotype of embryos lacking either Drk or Sos activity, as well as by the phenotype of a D-raf mutation that abolishes binding of Ras1 to D-Raf. These findings indicate that full D-Raf activation requires input not only from Ras1 but also from an as yet uncharacterized Ras1-independent pathway. In addition to these molecules we have characterized the putative protein tyrosine phosphatase Corkscrew as a positive transducer downstream of Torso.

1995_Mol Repro Dev_Perrimon.pdf
Perrimon N. Hedgehog and beyond. Cell. 1995;80 (4) :517-20. 1995_Cell_Perrimon.pdf
Siegfried E, Perrimon N. Drosophila wingless: a paradigm for the function and mechanism of Wnt signaling. Bioessays. 1994;16 (6) :395-404. Abstract

The link between oncogenesis and normal development is well illustrated by the study of the Wnt family of proteins. The first Wnt gene (int-1) was identified over a decade ago as a proto-oncogene, activated in response to proviral insertion of a mouse mammary tumor virus. Subsequently, the discovery that Drosophila wingless, a developmentally important gene, is homologous to int-1 supported the notion that int-1 may have a role in normal development. In the last few years it has been recognized that int-1 and Wingless belong to a large family of related glyco-proteins found in vertebrates and invertebrates. In recognition of this, members of this family have been renamed Wnts, an amalgam of int and Wingless. Investigation of Wnt genes in Xenopus and mouse indicates that Wnts have a role in cell proliferation, differentiation and body axis formation. Further analysis in Drosophila has revealed that Wingless function is required in several developmental processes in the embryo and imaginal discs. In addition, a genetic approach has identified some of the molecules required for the transmission and reception of the Wingless signal. We will review recent data which have contributed to our growing understanding of the function and mechanism of Drosophila Wingless signaling in cell fate determination, growth and specification of pattern.

Perrimon N. The genetic basis of patterned baldness in Drosophila. Cell. 1994;76 (5) :781-4. 1994_Cell_Perrimon.pdf
Perrimon N, Desplan C. Signal transduction in the early Drosophila embryo: when genetics meets biochemistry. Trends Biochem Sci. 1994;19 (11) :509-13. Abstract

An elegant combination of genetic and biochemical approaches has been used to investigate a variety of signal transduction pathways in developmental processes. Here, we describe the 'terminal' signaling system in the Drosophila embryo, which is responsible for pattern formation in the polar regions of the embryo. This pathway involves a membrane-bound receptor tyrosine kinase (RTK) that is similar to other Drosophila RTKs, such as sevenless, and the mammalian RTKs, such as the epidermal growth factor or platelet-derived growth factor receptors.

1994_Trends Biochem_Perrimon.pdf
Perrimon N. Signalling pathways initiated by receptor protein tyrosine kinases in Drosophila. Curr Opin Cell Biol. 1994;6 (2) :260-6. Abstract

The isolation and characterization of Drosophila mutations in receptor protein tyrosine kinases (RPTKs) have allowed a detailed analysis of the cellular processes regulated by these proteins. Recent investigations have identified a number of putative ligands involved in the activation of the receptors, and have demonstrated that these RPTKs trigger an evolutionarily conserved biochemical pathway. In addition to molecules previously identified from vertebrate studies, i.e. Grb2, Sos, Ras-Gap, p21ras, Raf, MEK and MAPK, genetic studies have suggested that two novel proteins, the protein tyrosine phosphatase (PTPase) Csw and the transmembrane protein Rho, are involved in RPTK signalling.

1994_Curr Opin Cell Bio_Perrimon.pdf
Duffy JB, Perrimon N. The torso pathway in Drosophila: lessons on receptor tyrosine kinase signaling and pattern formation. Dev Biol. 1994;166 (2) :380-95. Abstract

Pattern formation at the anterior and posterior termini of the Drosophila embryo involves intercellular communication via the Torso receptor tyrosine kinase (RTK). Recent advances in the understanding of Torso signaling has provided further support for the conservation of a signal transduction cassette downstream of RTKs. In addition, the analysis of the Torso pathway has begun to reveal general molecular mechanisms by which cells may impart patterning information to their neighbors through the use of RTKs.

1994_Dev Bio_Duffy.pdf
Noll E, Perkins LA, Mahowald AP, Perrimon N. Approaches to identify genes involved in Drosophila embryonic CNS development. J Neurobiol. 1993;24 (6) :701-22. Abstract

Many of the steps involved in formation of the Drosophila embryonic central nervous system (CNS) have been identified by both descriptive and experimental studies. In this review we will describe the various approaches that have been used to identify molecules involved in CNS development and the advantages and disadvantages of each of them. Our discussion will by no means be exhaustive; but rather we will discuss our experiences with each approach and provide an overview of what has been learned by using these methodologies. Finally, we will discuss methods that have been recently developed and how they are likely to provide further insight into CNS development.

1993_J Neurobiol_Noll.pdf
van den Heuvel M, Klingensmith J, Perrimon N, Nusse R. Cell patterning in the Drosophila segment: engrailed and wingless antigen distributions in segment polarity mutant embryos. Dev Suppl. 1993;:105-14. Abstract

By a complex and little understood mechanism, segment polarity genes control patterning in each segment of the Drosophila embryo. During this process, cell to cell communication plays a pivotal role and is under direct control of the products of segment polarity genes. Many of the cloned segment polarity genes have been found to be highly conserved in evolution, providing a model system for cellular interactions in other organisms. In Drosophila, two of these genes, engrailed and wingless, are expressed on either side of the parasegment border. wingless encodes a secreted molecule and engrailed a nuclear protein with a homeobox. Maintenance of engrailed expression is dependent on wingless and vice versa. To investigate the role of other segment polarity genes in the mutual control between these two genes, we have examined wingless and engrailed protein distribution in embryos mutant for each of the segment polarity genes. In embryos mutant for armadillo, dishevelled and porcupine, the changes in engrailed expression are identical to those in wingless mutant embryos, suggesting that their gene products act in the wingless pathway. In embryos mutant for hedgehog, fused, cubitus interruptus Dominant and gooseberry, expression of engrailed is affected to varying degrees. However wingless expression in the latter group decays in a similar way earlier than engrailed expression, indicating that these gene products might function in the maintenance of wingless expression. Using double mutant embryos, epistatic relationships between some segment polarity genes have been established. We present a model showing a current view of segment polarity gene interactions.

1993_DevSuppl_van den Heuvel.pdf
Lu X, Perkins LA, Perrimon N. The torso pathway in Drosophila: a model system to study receptor tyrosine kinase signal transduction. Dev Suppl. 1993;:47-56. Abstract

In the Drosophila embryo, specification of terminal cell fates that result in the formation of both the head (acron) and tail (telson) regions is under the control of the torso (tor) receptor tyrosine kinase. The current knowledge suggests that activation of tor at the egg pole initiates a signal transduction pathway that is mediated sequentially by the guanine nucleotide releasing factor son of sevenless (Sos), the p21Ras1 GTPase, the serine/threonine kinase D-raf and the tyrosine/threonine kinase MAPKK (Dsor1). Subsequently, it is postulated that activation, possibly by phosphorylation, of a transcription factor at the egg poles activates the transcription of the terminal gap genes tailless and huckebein. These gap genes, which encode putative transcription factors, then control the expression of more downstream factors that ultimately result in head and tail differentiation. Also involved in tor signaling is the non-receptor protein tyrosine phosphatase corkscrew (csw). Here, we review the current model and discuss future research directions in this field.

1993_Dev Suppl_Lu.pdf
Perrimon N. The torso receptor protein-tyrosine kinase signaling pathway: an endless story. Cell. 1993;74 (2) :219-22. 1993_Cell_Perrimon.pdf
Finkelstein R, Perrimon N. The molecular genetics of head development in Drosophila melanogaster. Development. 1991;112 (4) :899-912. 1991_Dev_Finkelstein.pdf