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. New advances in Drosophila provide opportunities to study gene functions. Proc Natl Acad Sci U S A. 1998;95 (17) :9716-7. 1998_PNAS_Perrimon.pdf
Perrimon N, Duffy JB. Sending all the right signals. Nature. 1998;396 (6706) :18-9. 1998_Nat_Perrimon.pdf
Goode S, Perrimon N. Brainiac and Fringe are pioneer proteins that impart specificity to Notch signals during Drosophila development. In: Symposia on Quantitative Biology. Cold Spring Harbor; 1998. p. 177-184. 1997_CSHQB_Goode.pdf
Mogila V, Bellaiche Y, Perrimon N. Expression of I-Sce.I in Drosophila to study Double Stand Breaks. In: DNA Repair Protocols: Eukaryotic Systems (Methods in Molecular Biology) . Humana Press; 1998. p. 439-445.
Li W, Skoulakis EM, Davis RL, Perrimon N. The Drosophila 14-3-3 protein Leonardo enhances Torso signaling through D-Raf in a Ras 1-dependent manner. Development. 1997;124 (20) :4163-71. Abstract

14-3-3 proteins have been shown to interact with Raf-1 and cause its activation when overexpressed. However, their precise role in Raf-1 activation is still enigmatic, as they are ubiquitously present in cells and found to associate with Raf-1 in vivo regardless of its activation state. We have analyzed the function of the Drosophila 14-3-3 gene leonardo (leo) in the Torso (Tor) receptor tyrosine kinase (RTK) pathway. In the syncytial blastoderm embryo, activation of Tor triggers the Ras/Raf/MEK pathway that controls the transcription of tailless (tll). We find that, in the absence of Tor, overexpression of leo is sufficient to activate tll expression. The effect of leo requires D-Raf and Ras1 activities but not KSR or DOS, two recently identified essential components of Drosophila RTK signaling pathways. Tor signaling is impaired in embryos derived from females lacking maternal expression of leo. We propose that binding to 14-3-3 by Raf is necessary but not sufficient for the activation of Raf and that overexpressed Drosophila 14-3-3 requires Ras1 to activate D-Raf.

Hou XS, Goldstein ES, Perrimon N. Drosophila Jun relays the Jun amino-terminal kinase signal transduction pathway to the Decapentaplegic signal transduction pathway in regulating epithelial cell sheet movement. Genes Dev. 1997;11 (13) :1728-37. Abstract

We have characterized mutations in the Drosophila homolog of the mammalian proto-oncogene c-Jun gene (Djun). We demonstrate that DJUN in the embryo is a downstream target of the JNK signal transduction pathway during dorsal closure formation, and that the function of the JNK/DJUN pathway is to control the localized expression of decapentalegic (dpp), a member of the TGF-beta growth factor family. In contrast to previous observations, we find that both in the embryo and during photoreceptor cell determination, DJUN is not regulated by a pathway that involves MAPK.

1997_Genes Dev_Hou.pdf
Häcker U, Lin X, Perrimon N. The Drosophila sugarless gene modulates Wingless signaling and encodes an enzyme involved in polysaccharide biosynthesis. Development. 1997;124 (18) :3565-73. Abstract

We have identified and characterized a Drosophila gene, which we have named sugarless, that encodes a homologue of vertebrate UDP-glucose dehydrogenase. This enzyme is essential for the biosynthesis of various proteoglycans, and we find that in the absence of both maternal and zygotic activities of this gene, mutant embryos develop with segment polarity phenotypes reminiscent to loss of either Wingless or Hedgehog signaling. To analyze the function of Sugarless in cell-cell interaction processes, we have focused our analysis on its requirement for Wingless signaling in different tissues. We report that sugarless mutations impair signaling by Wingless, suggesting that proteoglycans contribute to the reception of Wingless. We demonstrate that overexpression of Wingless can bypass the requirement for sugarless, suggesting that proteoglycans modulate signaling by Wingless, possibly by limiting its diffusion and thereby facilitating the binding of Wingless to its receptor. We discuss the possibility that tissue-specific regulation of proteoglycans may be involved in regulating both Wingless short- or long-range effects.

Eberl DF, Duyk GM, Perrimon N. A genetic screen for mutations that disrupt an auditory response in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1997;94 (26) :14837-42. Abstract

Hearing is one of the last sensory modalities to be subjected to genetic analysis in Drosophila melanogaster. We describe a behavioral assay for auditory function involving courtship among groups of males triggered by the pulse component of the courtship song. In a mutagenesis screen for mutations that disrupt the auditory response, we have recovered 15 mutations that either reduce or abolish this response. Mutant audiograms indicate that seven mutants reduced the amplitude of the response at all intensities. Another seven abolished the response altogether. The other mutant, 5L3, responded only at high sound intensities, indicating that the threshold was shifted in this mutant. Six mutants were characterized in greater detail. 5L3 had a general courtship defect; courtship of females by 5L3 males also was affected strongly. 5P1 males courted females normally but had reduced success at copulation. 5P1 and 5N18 showed a significant decrement in olfactory response, indicating that the defects in these mutations are not specific to the auditory pathway. Two other mutants, 5M8 and 5N30, produced amotile sperm although in 5N30 this phenotype was genetically separable from the auditory phenotype. Finally, a new adult circling behavior phenotype, the pirouette phenotype, associated with massive neurodegeneration in the brain, was discovered in two mutants, 5G10 and 5N18. This study provides the basis for a genetic and molecular dissection of auditory mechanosensation and auditory behavior.

Goode S, Perrimon N. Inhibition of patterned cell shape change and cell invasion by Discs large during Drosophila oogenesis. Genes Dev. 1997;11 (19) :2532-44. Abstract

Drosophila Discs large (Dlg) is a tumor suppressor gene whose loss in epithelial tissues causes disrupted cell polarity and increased cell proliferation. A human Dlg homolog, hDlg, has been implicated in tumorigenic processes via its association with the product of the Adenomatous Polyposis Coli (APC) gene. We show for the first time that Drosophila Dlg is required to block cell invasion. Loss of dlg activity during oogenesis causes follicle cells to change shape and invade in a pattern similar to border cells, a small population of cells that break from the post-mitotic follicular epithelium during wild-type oogenesis, yet dlg mutant cells have not adopted a border cell fate. Both functional and morphological evidence indicates that cooperation between germ cell and follicle cell Dlg, probably mediated by Dlg PDZ domains, is crucial for regulating cell mixing, suggesting a novel developmental mechanism and mode of action for the Dlg family of molecules. These findings suggest that Dlg does not simply inhibit individual cell behaviors during oogenesis, but rather acts in a developmental pathway essential for blocking cell proliferation and migration in a spatio-temporally defined manner. A model for Dlg action in blocking cell invasion is presented.

1997_Genes Dev_Goode.pdf
Hou XS, Perrimon N. The JAK-STAT pathway in Drosophila. Trends Genet. 1997;13 (3) :105-10. Abstract

Recent studies in Drosophila have identified a single JAK and a single STAT protein. Genetic and biochemical analyses reveal that these two proteins operate in the same signal transduction pathway. Phenotypic analyses of JAK and STAT mutants implicate this pathway in a number of developmental decisions, in particular the regulation of pair-rule genes and fly hematopoiesis.

1997_Trends Genet_Hou.pdf
Bellaiche Y, Perrimon N. [La voie de signalisation Wingless chez la Drosophile] (French). Medecine Sciences . 1997;13 :165-174. 1997_Med Sci_Bellaiche.pdf
Eberl DF, Lorenz LJ, Melnick MB, Sood V, Lasko P, Perrimon N. A new enhancer of position-effect variegation in Drosophila melanogaster encodes a putative RNA helicase that binds chromosomes and is regulated by the cell cycle. Genetics. 1997;146 (3) :951-63. Abstract

In Drosophila melanogaster, position-effect variegation of the white gene has been a useful phenomenon by which to study chromosome structure and the genes that modify it. We have identified a new enhancer of variegation locus, Dmrnahel (hel). Deletion of mutation of hel enhances white variegation, and this can be reversed by a transformed copy of hel+. In the presence of two endogenous copies, the transformed hel+ behaves as a suppressor of variegation. hel is an essential gene and functions both maternally and zygotically. The HEL protein is similar to known RNA helicases, but contains an unusual variant (DECD) of the DEAD motif common to these proteins. Potential HEL homologues have been found in mammals, yeast and worms. HEL protein associates with salivary gland chromosomes and locates to nuclei of embryos and ovaries, but disappears in mitotic domains of embryos as chromosomes condense. We propose that the HEL protein promotes an open chromatin structure that favors transcription during development by regulating the spread of heterochromatin, and that HEL is regulated by, and may have a role in, the mitotic cell cycle during embryogenesis.

Yu Y, Li W, Su K, Yussa M, Han W, Perrimon N, et al. The nuclear hormone receptor Ftz-F1 is a cofactor for the Drosophila homeodomain protein Ftz. Nature. 1997;385 (6616) :552-5. Abstract

Homeobox genes specify cell fate and positional identity in embryos throughout the animal kingdom. Paradoxically, although each has a specific function in vivo, the in vitro DNA-binding specificities of homeodomain proteins are overlapping and relatively weak. A current model is that homeodomain proteins interact with cofactors that increase specificity in vivo. Here we use a native binding site for the homeodomain protein Fushi tarazu (Ftz) to isolate Ftz-F1, a protein of the nuclear hormone-receptor superfamily and a new Ftz cofactor. Ftz and Ftz-F1 are present in a complex in Drosophila embryos. Ftz-F1 facilitates the binding of Ftz to DNA, allowing interactions with weak-affinity sites at concentrations of Ftz that alone bind only high-affinity sites. Embryos lacking Ftz-F1 display ftz-like pair-rule cuticular defects. This phenotype is a result of abnormal ftz function because it is expressed but fails to activate downstream target genes. Cooperative interaction between homeodomain proteins and cofactors of different classes may serve as a general mechanism to increase HOX protein specificity and to broaden the range of target sites they regulate.

Engstrom L, Noll E, Perrimon N. Paradigms to study signal transduction pathways in Drosophila. In: Curr Top Dev Biol. 1997. p. 229-61.
Perrimon N, Perkins LA. There must be 50 ways to rule the signal: the case of the Drosophila EGF receptor. Cell. 1997;89 (1) :13-6. 1997_Cell_Perrimon.pdf
Häcker U, Perrimon N. Components of the Wnt signaling pathway. In: Codwin P, Klymkowsky M. Cytoskeletal-Membrane and Signal Transduction. Landes Bioscience ; 1997. p. 61-72.
Li W, Perrimon N. Specificity of receptor tyrosine signaling pathways: Lessons from Drosophila. In: Genetic Engineering: Principles and Methods. Plenum Press; 1997. p. 167-182.
Chou TB, Perrimon N. The autosomal FLP-DFS technique for generating germline mosaics in Drosophila melanogaster. Genetics. 1996;144 (4) :1673-9. Abstract

The production of female germline chimeras is invaluable for analyzing the tissue specificity of recessive female sterile mutations as well as detecting the maternal effect of recessive zygotic lethal mutations. Previously, we developed the "FLP-DFS" technique to efficiently generate germline clones. This technique uses the X-linked germline-dependent dominant female sterile mutation ovoD1 as a selection for the detection of germline recombination events, and the FLP-FRT recombination system to promote site-specific chromosomal exchange. This method allows the efficient production of germline mosaics only on the X chromosome. In this paper we have built chromosomes that allow the use of this technique to the autosomes. We describe the various steps involved in the development of this technique as well as the properties of the chromosomes utilized.

Klingensmith J, Yang Y, Axelrod JD, Beier DR, Perrimon N, Sussman DJ. Conservation of dishevelled structure and function between flies and mice: isolation and characterization of Dvl2. Mech Dev. 1996;58 (1-2) :15-26. Abstract

The segment polarity gene dishevelled (dsh) of Drosophila is required for pattern formation of the embryonic segments and the adult imaginal discs. dsh encodes the earliest-acting and most specific known component of the signal transduction pathway of Wingless, an extracellular signal homologous to Wnt1 in mice. We have previously described the isolation and characterization of the Dvl1 mouse dsh homolog. We report here the isolation of a second mouse dsh homolog, Dvl2, which maps to chromosome 11. The Dvl2 amino acid sequence is equally related to the dsh sequence as is that of Dvl1, but Dvl2 is most similar to the Xenopus homolog Xdsh. However, unlike the other vertebrate dsh homologs. Like the other genes, Dvl2 is ubiquitously expressed throughout most of embryogenesis and is expressed in many adult organs. We have developed an assay for dsh function in fly embryos, and show that Dvl2 can partially rescue the segmentation defects of embryos devoid of dsh. Thus, Dvl2 encodes a mammalian homolog of dsh which can transduce the Wingless signal.

1996_Mech Dev_Klingensmith.pdf