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Biomedical subjects

N Perrimon

Publications and source records attributed to N Perrimon.

At least 109 records · Page 6Linked to original sources
PubMed1995

The porcupine gene is required for wingless autoregulation in Drosophila.

The Drosophila segment polarity gene wingless (wg) is required in the regulation of engrailed (en) expression and the determination of cell fates in neighboring cells. This paracrine wg activity also regulates transcription of wg itself, through a positive feedback loop including en activity. In addition, wg has a second, more direct autoregulatory requirement that is distinct from the en-dependent feedback loop. Four gene products, encoded by armadillo (arm), dishevelled (dsh), porcupine (porc) and zeste-white 3 (zw3), have been previously implicated as components of wg paracrine signaling. Here we have used three different assays to assess the requirements of these genes in the more direct wg autoregulatory pathway. While the activities of dsh, zw3 and arm appear to be specific to the paracrine feedback pathway, the more direct autoregulatory pathway requires porc.

Animals↗
PubMed1995

Dual functions of wingless in the Drosophila leg imaginal disc.

The Drosophila gene wingless is a member of the Wnt gene family, a group of genes that are involved in embryonic development and the regulation of cell proliferation. wingless encodes a secreted glycoprotein that plays a role in embryogenesis as well as in the development of adult structures. In the primordia of the adult limbs, the imaginal discs, wingless is expressed in an anterior ventral sector and is required for specification of ventral fate. Ectopic expression of low levels of Wingless in the leg discs leads to partial ventralization and outgrowths of the proximodistal axis. Wingless has thus been proposed to specify ventral fate in a concentration dependent manner (i.e., as a morphogen) and to organize the proximodistal axis. We have extended the analysis of Wingless function in the leg primordium through targeted ectopic expression. We find that Wingless has two functions in the leg disc. In the specification of ventral fate, our data indicate that Wingless does not function as a morphogen but instead appears to collaborate with other factors. In addition to its role in ventral fate specification, Wingless inhibits the commitment of dorsal cells toward a determined state and influences the regulation of proliferation. We propose a model in which Wingless achieves separate functions via spatially regulated mechanisms and discuss the significance of these functions during axial patterning and organization.

Animals↗
PubMed1995

Dorsalizing and neuralizing properties of Xdsh, a maternally expressed Xenopus homolog of dishevelled.

Signaling factors of the Wnt proto-oncogene family are implicated in dorsal axis formation during vertebrate development, but the molecular mechanism of this process is not known. Studies in Drosophila have indicated that the dishevelled gene product is required for wingless (Wnt1 homolog) signal transduction. We demonstrate that injection of mRNA encoding a Xenopus homolog of dishevelled (Xdsh) into prospective ventral mesodermal cells triggers a complete dorsal axis formation in Xenopus embryos. Lineage tracing experiments show that cells derived from the injected blastomere contribute to anterior and dorsal structures of the induced axis. In contrast to its effect on mesoderm, overexpression of Xdsh mRNA in prospective ectodermal cells triggers anterior neural tissue differentiation. These studies suggest that Wnt signal transduction pathway is conserved between Drosophila and vertebrates and point to a role for maternal Xdsh product in dorsal axis formation and in neural induction.

Adaptor Proteins, Signal Transducing↗
PubMed1994

A temperature-sensitive MEK mutation demonstrates the conservation of the signaling pathways activated by receptor tyrosine kinases.

MEK, a dual specificity threonine/tyrosine kinase, has been postulated to be a convergent point for signaling from receptor protein tyrosine kinases (RTKs) and G-protein-coupled receptors. In contrast to yeast and mammalian cells where several MEKs have been isolated, only one Drosophila MEK (D-Mek) has been characterized to date. Previous studies have shown that D-Mek acts in the Torso RTK signaling pathway. To demonstrate that D-Mek also operates downstream of other RTKs, we generated a temperature-sensitive allele of D-mek (D-mekts) by site-directed mutagenesis based on the amino acid change of a yeast cdc2ts mutation. Using D-mekts, we show that in addition to its role in Torso signaling, D-Mek operates in the Sevenless and in the Drosophila epidermal growth factor RTK pathways. Because loss-of-function mutations in D-mek and the upstream receptors give rise to similar phenotypes, it suggests that D-mek is the only MEK activated by Drosophila RTKs. In addition, we demonstrate that different RTK pathways respond differently to alteration in D-Mek activity.

Alleles↗
PubMed1994

Genetic and molecular analyses of mutations involved in Drosophila raf signal transduction.

We have identified dominant mutations that suppress the lethality associated with an R217-->L mutation in the GTP.Ras binding region (CR1) of the Drosophila raf (D-raf) serine/threonine kinase. Four intragenic and seven extragenic suppressors were recovered. Each of the four intragenic mutations contains one compensatory amino acid change located in either the CR1 or the kinase domain of D-raf. The seven extragenic suppressors represent at least four genetic loci whose effects strongly suggest that they participate in both the sevenless and Drosophila EGF receptor (DER) signaling pathways. One of these mutations, Su(D-raf)34B, is an allele of D-mek which encodes the known signaling molecule MAPK kinase (MEK). A D83V mutation in D-MEK is identified and shown to be sufficient to confer the dominant activity of Su(D-raf)34B.

Amino Acid Sequence↗
PubMed1994

Raf acts downstream of the EGF receptor to determine dorsoventral polarity during Drosophila oogenesis.

In Drosophila, as in mammalian cells, the Raf serine/threonine kinase appears to act as a common transducer of signals from several different receptor tyrosine kinases. We describe a new role for Raf in Drosophila development, showing that Raf acts in the somatic follicle cells to specify the dorsoventral polarity of the egg. Targeted expression of activated Raf (Rafgof) within follicle cells is sufficient to dorsalize both the eggshell and the embryo, whereas reduced Raf activity ventralizes the eggshell. We show that Raf functions downstream of the EGF receptor to instruct the dorsal follicle cell fate. In this assay, human and Drosophila Rafgof are functionally similar, in that either can induce ventral follicle cells to assume a dorsal fate.

Animals↗
PubMed1994

Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila.

We describe the characterization of the Drosophila gene, hopscotch (hop), which is required maternally for the establishment of the normal array of embryonic segments. In hop embryos, although expression of the gap genes appears normal, there are defects in the expression patterns of the pair-rule genes even-skipped, runt, and fushi tarazu, as well as the segment-polarity genes engrailed and wingless. We demonstrate that the effect of hop on the expression of these genes is stripe-specific. The hop gene encodes a putative nonreceptor tyrosine kinase of the Janus kinase family, based on an internal duplication of the catalytic domain. We present a model in which the Hop tyrosine kinase is involved in the control of pair-rule gene transcription in a stripe-specific manner. Our results provide the first evidence for stripe-specific regulation of pair-rule genes by a tyrosine kinase.

Amino Acid Sequence↗
PubMed1994

Components of wingless signalling in Drosophila.

The determination of specific cell fates and polarity within each segmental unit of the Drosophila embryo involves the products of the segment polarity genes. One of these, wingless (wg), encodes a secreted protein that is homologous to the mammalian proto-oncogene Wnt-1 (refs 4, 5). In the embryonic epidermis, wg is expressed in a single row of cells within each segmental unit, although its activity is required for the correct patterning of most of the epidermis. Initially Wg signals to adjacent posterior cells, maintaining engrailed (en) expression. Later during embryogenesis, wg specifies the differentiation of naked cuticle. Wg signalling functions by inactivating or antagonizing the activity of zestewhite 3 (zw3). We have investigated the requirement in the Wg signal transduction pathway for the three genes armadillo (arm), dishevelled (dsh) and porcupine (porc), all of which have embryonic mutant phenotypes similar to wg. Our results indicate that dsh and porc act upstream of zw3, and arm acts downstream of zw3.

Adaptor Proteins, Signal Transducing↗
PubMed1994

dishevelled and armadillo act in the wingless signalling pathway in Drosophila.

The Wnt genes encode conserved secreted proteins that play a role in normal development and tumorigenesis. Little is known about the signal transduction pathways of Wnt gene products. One of the best characterized Wnt family members is the Drosophila segment polarity gene wingless. We have investigated whether segment polarity genes with a wingless-like phenotype mediate the wingless signal. We used a wingless transgene controlled by a heat-shock promoter for genetic epistasis experiments. We show that wingless acts through dishevelled and armadillo to affect the expression of the homeobox gene engrailed and cuticle differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Drosophila wingless: a paradigm for the function and mechanism of Wnt signaling.

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.

Animals↗
PubMed1994

Isolation and characterization of a mouse homolog of the Drosophila segment polarity gene dishevelled.

In the Drosophila embryo dishevelled (dsh) function is required by target cells in order to respond to wingless (wg, the homolog of Wnt-1), demonstrating a role for dsh in Wnt signal transduction. We have isolated a mouse homolog of the Drosophila dsh segment polarity gene. The 695-amino-acid protein encoded by the mouse dishevelled gene (Dvl-1) shares 50% identity (65% similarity) with dsh. Similarity searches of protein and DNA data bases revealed that Dvl-1 encodes an otherwise novel polypeptide. While no functional motifs were identified, one region of Dvl-1 was found to be similar to a domain of discs large-1 (dlg), a Drosophila tumor suppressor gene. In the embryo, Dvl-1 is expressed in most tissues, with uniformly high levels in the central nervous system. From 7.5 days postcoitum Dvl-1 is expressed throughout the developing brain and spinal cord, including those regions expressing Wnt-1 and En. Expression of Dvl-1 in adult mice was found to be widespread, with brain and testis exhibiting the highest levels. The majority of Dvl-1 expression in the adult cerebellum is in the granular cell layer, similar to the pattern seen for engrailed-2 (En-2). Throughout postnatal development of the brain Dvl-1 is highly expressed in areas of high neuronal cell density.

Adaptor Proteins, Signal Transducing↗
PubMed1994

The torso pathway in Drosophila: lessons on receptor tyrosine kinase signaling and pattern formation.

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.

Animals↗
PubMed1994

Signalling pathways initiated by receptor protein tyrosine kinases in Drosophila.

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.

Animals↗
PubMed1994

Signal transduction in the early Drosophila embryo: when genetics meets biochemistry.

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.

Animals↗
PubMed1994

The Drosophila segment polarity gene dishevelled encodes a novel protein required for response to the wingless signal.

The Drosophila Wnt-1 homolog, wingless (wg), is involved in the signaling of patterning information in several contexts. In the embryonic epidermis, Wg protein is secreted and taken up by neighboring cells, in which it is required for maintenance of engrailed transcription and accumulation of Armadillo protein. The dishevelled (dsh) gene mediates these signaling events as well as wg-dependent induction across tissue layers in the embryonic midgut. dsh is also required for the development processes in which wg functions in adult development. Overall, cells lacking dsh are unable to adopt fates specified by Wg. dsh functions cell autonomously, indicating that it is involved in the response of target cells to the Wg signal. dsh is expressed uniformly in the embryo and encodes a novel protein with no known catalytic motifs, although it shares a domain of homology with several junction-associated proteins. Our results demonstrate that dsh encodes a specific component of Wg signaling and illustrate that Wnt proteins may utilize a novel mechanism of extracellular signal transduction.

Adaptor Proteins, Signal Transducing↗
PubMed1993

Mutations in the segment polarity genes wingless and porcupine impair secretion of the wingless protein.

We have characterized the molecular nature of mutations in wingless (wg), a segment polarity gene acting during various stages of Drosophila development. Embryo-lethal alleles have undergone mutations in the protein-encoding domain of the gene, including deletions and point mutations of conserved residues. In a temperature sensitive mutation, a conserved cysteine residue is replaced by a serine. In embryo-viable alleles, the wg transcriptional unit is not affected. Immunostaining of mutant embryos shows that the embryo-lethal alleles produce either no wg antigen or a form of the protein that is retained within cells. Interestingly, embryos mutant for the segment polarity gene porcupine show a similar retention of the wg antigen. We have also transfected wild type wg alleles into Drosophila tissue culture cells, which then display wg protein on the cell surface and in the extracellular matrix. In similar experiments with mutant alleles, the proteins are retained in intracellular compartments and appear not to be secreted. These data provide further evidence that wg acts as a secreted factor and suggest that porcupine provides an accessory function for wg protein secretion or transport.

Alleles↗