Roles of the JNK signaling pathway in Drosophila morphogenesis

Roles of the JNK signaling pathway in Drosophila morphogenesis

466 Roles of the JNK signaling pathway in Drosophila Stbphane NoseHi*? and Fraqois Agnkst Epithelial cell differentiation and morphogenesis many a...

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466

Roles of the JNK signaling pathway in Drosophila Stbphane NoseHi*? and Fraqois Agnkst Epithelial

cell differentiation

and morphogenesis

many aspects of metazoan studies in Drosophila have amino-terminal kinase epithelial morphogenesis dorsal

closure

and

development. revealed that

during

participates

in the control

epithelial

of planar

Opinion

in Genetics

polarity

studies have linked the and Frizzled pathways degree of integrative

in

morphogenesis.

Addresses *Department of Genetics, Harvard Medical School, Avenue, Boston, Massachussetts 02115, USA; e-mail: [email protected] fCentre de Biologie du Developpement, UMR5547 Narbonne, 31062 Toulouse Cedex, France Current

in

(JNK) signaling pathway regulates during the process of embryonic

in several tissues. Importantly, these JNK pathway to the decapentaplegic these processes, suggesting a high signaling

are crucial

Recent genetic the conserved Jun

& Development

1999,

200 Longwood

1 16, route de 9:466-472

http://biomednet.com/elecref/0959437X00900466 0 Elsevier

Science

Ltd ISSN

Abbreviations DC dorsal closure decapentaplegic dw JNK Jun amino-terminal MAPK mitogen-activated mbc myoblast city LE leading edge

0959-437X

kinase protein kinase

Introduction The study of signal transduction pathways has provided nice models of cell communication controlling differentiation, patterning and development. Among the known signaling cascades, the mitogen-activated protein kinase (MAPK) pathways have rapidly attracted a wide interest for several reasons [l]. First, at least three related but different MAPK pathways -the extracellular regulated kinase [ERK], Jun amino-terminal kinase and p38 -can be distinguished in metazoa that mediate specific cell and developmental responses. Second, MAPK pathways are versatile: for example, the JNK pathway can transduce signals of a very diverse nature, including unrelated extracellular stresses as well as developmental signals [l-3]. Finally, the rapid accumulation of information from molecular cloning of components of MAPK pathways in several species has revealed a strong evolutionary conservation, which may ultimately provide a wide view of the biology of these pathways. DrosopMa can be used as a good genetic model to study the role of MAPK pathways in development, an approach that is well supported by the existence in flies of homologous signaling cascades [4,5,6’]. In this review, we discuss the most recent studies on the role of JNK signaling in dorsal closure and also new emerging roles of this pathway in epithelial morphogenesis.

The Drosophila dorsal closure

morphogenesis

JNK cascade

and

During the first half of embryonic development, the dorsal part of the embryo is occupied by a stretched epithelium (the amnioserosa), which by mid-embryogenesis is progressively covered by lateral ectodermal cells undergoing dorsal closure (DC): these epithelial cells elongating dorsally and moving in concert toward the dorsal midline where they fuse at the end of the process [2,7-91. Several mutations collectively known as the ‘dorsal open’ group affect the process of dorsal closure (Table l), which represent a unique collection of genes with specific functions in morphogenesis. A major goal is to determine the molecular and genetic interactions organizing these functions in development. An important initial step in DC is the differentiation within each lateral epithelium of a line of cells forming a leading edge (LE). These cells, which contact the amnioserosa, are the site of JNK activity during DC [Z]. The JNK pathway is best viewed as a linear cascade, comprising the hemipterous/DJNKK [lo], baskef/DJNK [11,12] and Djun [13-151 genes (Figure 1). When mutated, these genes lead to a typical ‘dorsal open’ phenotype reflecting a failure of the lateral ectoderm to move dorsally. These defects are accompanied by aberrant accumulation of a number of membrane-associated products, including F-actin, nonmuscle myosin, fasciclin III and proteins containing phosphotyrosines. In addition, LE-specific expression of puckered and decapentapbgic (dpp), two targets of the JNK pathway (see below), is abolished [10,14-171. In vitro studies have shown that the Hemipterous (DJNKK) protein can phosphorylate Basket (DJNK) which, in turn, can activate Djun by phosphorylation [11,12,17]. In addition to Djun, two other transcription factors have been identified as essential for DC -the Drosophila homolog of Fos, Dfos protein anterior open [18,191, and the ETS-domain (aop)/yan [18]. Both Djun and Dfos act as positive regulators, probably through the formation of heterodimers, whereas aop functions as a negative regulator in the process. Overexpression of aop provokes DC defects, whereas expression of an activated form of Djun can rescue the DC defect associated with basket mutations [13,15]. These data, together with recent knockouts in mouse [20,21], clearly demonstrate that the JNK pathway and&n have essential functions during normal development. More recently, new upstream components have been identified. midapen encodes a steZO-related kinase of the SPS-1 family [ZZ’], with homologs in vertebrates (NIK, Nck-inceracting kinase) and the nematode worm Caenorhabdits elegans (,mig-15). In contrast to other steZO-related molecules like DPAK [23], misshapen does not have a rac/cdc4Zbinding domain indicating that the two kinases function differently. Zygotic loss of misshapen function induces a dorsal-open

Roles

Figure

of the JNK signaling

pathway

in Drosophila

morphogenesis

Noselli

and

Agnes

467

1

The Drosophila JNK pathway controls dorsal closure and planar polarity. During dorsal closure, the JNK signaling pathway is activated in the LE by an unknown signal, and one important outcome of this signaling activity is the induction of drop (the product of which is a TGF-6 homolog) expression in these cells. This coupling of JNK and dpp signaling pathways is proposed to control morphogenesis of the more lateral ectodermal cells by the dpp pathway. In addition to JNK signal transducers, membrane-associated proteins participate in the elaboration of normal JNK and cytoskeletal activities to realize a concerted movement. In planar polarity, the coupling of frizzledldishevelled and JNK activities signals the correct arrangement of cells within the plane in the eye imaginal disc. Arrows indicate activation and lines ending in a bar represent repressor functions. bsk, basket; Cno, Canoe; Cor, Coracle; Dlg, Discs large; DSH, dishevelled; Fz, Frizzled; hep, hemipterous; nrx, neurexin; msn, misshapen; put, puckered, put, punt; shn, schnurri; tkv, thickveins.

Wnt

? t

-Fz-

DRacl DrhoA

-

Dig

mbc

Cor nrx IV

Dracl MEKK

t hep/DJNKK

t hep/DJNKK

t bsk/DJNK

t bsk/DJNK

?

Cno 20-l

t Djun

4 tkv put shn Dfos

Planar

polarity

Dorsal

closure Current

phenotype and a reduction of dpp LE expression in some embryos. Genetic epistasis experiments are consistent with misshapen acting upstream of HEP, probably activating an as yet unknown MEKK [ZZ’]. In a two-hybrid screen using misshapen as a bait, a Drosophila TNF-receptor-associated factor (DTRAFl) has been identified [24’]. These proteins are proposed to link TNF receptors to the JNK pathway in inflammation. In mouse TRAFZ homozygous mutant cells, activation of the JNK pathway following exposure to TNF is abolished [25]. Database searches have revealed the presence of another TRAF gene in Drosophil’a (DTRAFZ), raising the possibility that several of these molecules may act in DC or that the JNK pathway may be activated by different TRAFs in different tissues [W]. However, a demonstration that DTRAFs act in the Drosophila JNK pathway awaits the isolation of mutations in these genes. In vertebrate cells, a role for the small GTPases of the Rho family in JNK activation and in the regulation of the actin cytoskeleton has been well documented [26,27]. In Drosophila, expression of dominant negative Dracl, Dcdc42 or DrhoA in the ectoderm leads to DC phenotypes [ 11,28,29’,30’] and embryos mutant for DRhoA have a mild dorsal-open phenotype [31]. Their role as potent JNK pathway activators in Drosophila is shown by the ability of activated DraclVlZ and Dcdc42VlZ to induce the expres-

Opinion

in Genetics

& Development

sion of puckered and dpp outside the LE, an activity that depends on the downstream activity of /zemipterow [16]. Interestingly, the effects of both molecules are slightly different, suggesting that they play only partly redundant roles in the process. Further support for this view is provided by monitoring the formation of the actin-myosin cytoskeleton when negative forms of Dracl, D&42 and DrhoA are differentially expressed in the LE: DraclNl7 disrupts actin and myosin assembly in the LE more efficiently than Dcdc4ZN17 [29’]. Dcdc42N17 also affects accumulation of DPAK, a potential Dracl/Dcdc42 effector, to downregulate cytoskeleton assembly. Surprisingly, the effects of DrhoAN19 on cytoskeletal assembly are restricted to cells flanking the segment borders. It will be interesting to confirm this result using DrhoA mutants and test the possibility that local changes along the AP axis may have a role in establishing a functional LE. Signaling at a border The accurate regulation of JNK activity in the LE is important to ensure proper morphogenesis, as illustrated by loss- and gain-of-function JNK pathway mutants. How is this activity regulated during DC? Although an activating signal for this pathway has not yet been identified in Drosophda, the phenotypic and molecular analysis ofpuckered revealed an important mechanism whereby JNK

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and developmental

mechanisms

activity is downregulated [16,32’]. In puckered embryos, closure proceeds almost normally and the main defect is a puckering of the dorsal midline [33]. This phenotype suggests that puckered is not essential for the spreading of the ectoderm. Interestingly, when the activity of the pathway is monitored using dpp and puckered itself, a novel phenotype is observed which is opposite to the one observed in hemipterous, basket or Djun mutants: both dpp and puckered are overexpressed in the LE [16,32’]. These observations indicate that puckered is a repressor of the JNK pathway in the LE. Consistent with this, cloning of the puckered gene revealed that it encodes a MAPK phosphatase of the VH-1 family [32’]. In extracts prepared from puckered mutant embryos, the activity of the DJNK/BSK protein is specifically elevated relative to wild type, whereas activity of the rolled/ERK MAPK remained constant. As expected of a negative regulator, overexpression of puckered leads to a strong dorsal-open phenotype [32’]. The existence of a puckered-dependent negative feedback loop controlling the level of JNK signaling activity in the LE may serve two important roles: the first one is to turn off signaling to stop the accompanying movement of lateral cells at the end of the process, thus promoting contact inhibition and suture of the LEs. Constitutive morphogenetic activity at the time of suture probably leads to a LE conflict at the midline and the resulting puckering. Second, the forces that drive movement need to have their strength regulated for coordinating lateral ectoderm’s pace, and a gradient of dpp, a Drosophila TGF-B homolog, is proposed to control these morphogenetic parameters remotely [Z]. Thus, coupling dpp expression to JNK activity in the LE is a nice mechanism that may create diversity in several related morphogenetic movements. Dorsal closure and the membrane Another class of mutants described in this section exhibit a clear dorsal open phenotype. In contrast to the JNK pathway genes described above, they affect only moderately if at all, the expression of dpp and puckered. These genes may therefore correspond to components acting dowstream of or parallel to the JNK pathway, although a direct regulatory link between JNK activation and the membrane is still lacking. An emerging view is that some membrane-associated proteins may provide a specialized environment for appropriate JNK and/or dpp signaling, as well as regulating the assembly of cytoskeletal complexes. The cell-shape changes by membrane and (Table l), like the two 20-l that link the [34,35’]. PDZ-domain tion that are generally where they appear to example by clustering synapse [36].

accompanying DC are mediated cytoskeletal effector proteins PDZ-domain proteins Canoe and membrane and JNK signaling proteins mediate complex formabound to the plasma membrane, assemble signaling activities, for receptors at the neuromuscular

Table 1 Dorsal closure

genes. Protein

Gene JNK pathway DrhoA Dracl Dcdc42 DPAK Dtrafl and 2 misshapen hemipterous basket Dfos Djun anterior open (AoplYan) puckered

dpp

function-homology

References

Small GTPase Small GTPase Small GTPase p21 -activated kinase TNF-receptor associated factor stelO-related kinase Jun amino-terminal kinase kinase Jun amino-terminal kinase AP-1 complex AP-1 complex ETS-domain Transcription factor Dual specificity MAPK Phosphatase (VH-1)

1311

EWI [281 1231 124’1 122’1 1101 [11,121

118,191 [13-151 1151 [32’1

pathway

d/w thickveins punt schnurri

TGF-5 TGF-jT Transcription

Membrane junctions canoe polychaetoid coracle neurexin IV dig mbc myospheroid scab Cytoskeleton actin zipper lethal(2)giant Others DCgl ribbon raw

ZO-1

AF6 homolog (PDZ domain) homolog (MAGUK, PDZ domain) 4-l protein Caspr homolog MAGUK (PDZ domain) Dock1 80 lntegrin j3 subunit lntegrin Q subunit

Non larvae

CTG F-$1 (type I) receptor (type II) receptor factor (zinc finger)

Filamentous actin muscle myosin heavy Pioneer protein

Collagen

IV ? ?

chain

[14-161 [6 l-651 [65-671 168-701

[34,35’1 135’1

[42,431 141

[411 [39,40-l [711

WI

191 [731

[741 1751

[751

Different classes of DC genes can be distinguished: genes involved signaling in the leading edge (JNK pathway) and genes that are proposed to respond to dpp in the lateral ectoderm (dpp pathway); and genes encoding membrane-associated proteins that are components of the cytoskeleton and/or the adherens and septate junctions. Genes in italics are candidate DC genes for which mutations have not yet been described that affect this process. Guestion marks indicate that the gene has not been cloned. References have been selected for those describing the role of the corresponding genes in DC.

in

Canoe and 20-l are co-localized at the adherens junctions and interact both genetically and biochemically [35’]. Homozygous canoe as well as a synthetic lethal canoe, polyckaetoid (pyd, the gene encoding Drosophdia 20-l) combination lead to dorsal-open embryos. Evidence that canoe, but also pyd, participate in JNK signaling is supported by genetic interactions with Aemipterous and basket in embryos and adults. Furthermore, packered and dpp expression is reduced but not abolished in canoe mutants. A proposed model is that a Canoe-20-l complex may assemble or cluster

Roles

of the JNK signaling

signaling molecules (receptor[s]?) at the adherens junction that promote JNK activity [35’]. DOCKl80, an SH3-containing protein, has been implicated in the regulation of cell morphology [37,38]. Myoblast city (mbc), a DrosopMa homolog of DOCK180, affects DC and a proportion of mbcmutant embryos adopt a rounded shape and express Fasciclin III abnormally [39]. In addition, these embryos accumulate lessfilamentous actin than the wild type. These cytoskeletal changes are thought to be mediated specifically by DRacl, asmbc strongly suppresses Dracl-mediated dominant phenotypes in the adult fly eye and specifically binds to Dracl in vitro [40’]. dpp expression in mbc mutant embryos is only moderately affected, suggesting that mbccontributes to JNK activation, possibly via Dracl. In support of this function, DOCK180 has been shown to activate JNKl specifically and induce an increase in c-Jun phosphorylation in a Racl-dependent manner [37]. Thus, mbc may contribute to the dual function of Dracl in DC, that is, by regulating both the cytoskeleton and JNK. Interestingly, the subcellular localization of mbc/DOCK180 to membrane ruffles suggestsa model in which compartmentalization of Dracl/mbc in separatepools may convey the two complementary functions [40’]. The septate junctions in insects are thought to be functionally equivalent to the tight junctions in vertebrate epithelial cells. Interestingly, three proteins that are associated with the septate junction, discs-large (dlg; [41]), coracle [42,43] and neurexin IV (nrx; [44]), cause DC defects when the corresponding gene is mutated. Both a’~ and wx are required for correct subcellular localization of coracle [45,46]. In vitro studies show that nrx and coracle interact and it is likely that dlg and coracle associate,as do their mammalian homologs [47,48]. These results suggest that maintenance of epithelium integrity via the septate junctions is crucial for morphogenesis. However, phenotypic analysis indicates that coracle, although an integral component of the septate junction, is not necessaryfor apical-basal polarity and epithelial integrity; rather, it is proposed that dpp signaling from the LE requires a unique apical environment, provided at least in part by coracle proteins [43]. JNK signaling

and tissue

polarity

Planar or tissue polarity is characterized by the orientation of hairs or cells perpendicular to the apical-basal axis [49,50]. In DrosopMa, tissue polarity is controlled by the seven-passfrizzled receptor [Sl] and, recently, several members of the JNK signaling pathway have been identified downstream of this protein. DRhoA, a small GTPase required in DC, was shown to control the rotation of ommatidia in eyes and the orientation of wing hairs in adult flies [31]. Furthermore, genetic interactions have indicated a role for hemipterozls, basket and Djun in mediating ftixded signaling for eye polarity. Indeed, the multi-domain dsh protein was identified in flies and

pathway

in

Drosophila morphogenesis

Noselli

and

Agrks

469

vertebrates as a crucial adapter linking frizded and the JNK pathway in tissue polarity [.52,53’,54’,55]. Interestingly, the DEP domain of a’i.rhrnelLed is specifically required for tissue polarity but not for wingless signaling, as demonstrated by structure-function analysis [53’,54’]. Moreover, the DEP domain was shown to target dishevelled to the membrane, suggesting that translocation is important for tissue polarity function and further cytoskeletal orientation [54’]. In Drosophda, d&?ee)eLedl,a mutation displaying tissue polarity defects only, interacts genetically with several members of the JNK pathway and maps in the DEP domain. In vitro, dishevelledl is no longer able to activate Djun phosphorylation, nor does a truncated form of Dvl (the mouse ortholog of dishevelled) in COS-7 cells [53’,55]. As /iemipterovs or basket mutants only have subtle tissue polarity phenotypes, it is proposed that d&eveLr’edcan activate several related JNK and/or p38 MAPKs that may act redundantly in tissue polarity [53’]. Strikingly, planar polarity is also observed in the LE, as reflected by the asymmetric localization of several proteins along the dorsal-ventral axis (dorsal accumulation of filamentous actin, myosin, DrosopMa p21-activated kinase, or dorsal exclusion of Fasciclin III and coracle; [8,9,23,42]). In JNK pathway mutants, like Djun andpuckered, asymmetric localization in the LE is lost [14,33] but aspuckered mutant embryos can still close the ectoderm, it is not clear whether asymmetric development is essential for LE function and DC. Interestingly, the fact that at least some members of the JNK pathway mediate Frizzled signaling raises the possibility that Frizzled or a Frizzled-like receptor may activate the DC pathway.

Conclusions

and perspectives

In conclusion, the studies of DC and tissue polarity illustrate JNK signaling versatility and how a single pathway may regulate different aspectsof epithelial morphogenesis. However, the JNK pathway is not essential for all epithelia in DrosopAda, indicating that other mechanisms remain to be discovered. One important future direction will certainly be the quest for signal(s) and receptor(s) acting in DC. On the basis of our current understanding of the JNK pathway in DrosopMa, it is tempting to speculate that related processes - that is, those morphogenetic movements employing epithelia with ‘free’ or differentiated edges [56], including metamorphosis (F Agnes et al., unpublished data), ventral enclosure in Caenor~abditus elegans [57], epiboly and wound-healing in vertebrates [58,59] - may also involve JNK signaling.

Acknowledgements We wish to thank D Gibbs and B Mathey-Prevost for critically reading the manuscript. S Noselli thanks N Perrimon for discussions. F Aants is supported by a fellowship from Ligue Nationale Contre le Can&. This work is supported by the Centre National de la Recherche Scientifique (CNRS), thd North Atlantic Treaty Organisation (NATO), Association pour la Recherche sur le Cancer and Ligue Contre le Cancer.

470

Pattern

formation

References Papers of particular have been highlighted l

**of

and

interest, as:

published

reading

within

the annual

period

J: Sounding the and inflammation.

2.

Noselli Genet

3.

Ip YT, Davis JD: Signal (JNK)-from inflammation 1998, 10:205-219.

19.

Zeitlinger Defective expression

20.

Yang D, Tournier C, Wysk M, Lu Flavell FL&Targeted disruption embryonic death, inhibition of activation, and defects in AP-1 Acad Sci USA 1997,94:3004-3009.

of review,

of special interest outstanding interest Kyriakis JM, Avruch activated by stress 271124313-24316.

5.

mechanisms

and recommended

1.

4.

developmental

alarm: protein kinase J B/o/ Chem 1996,

cascades 21.

S: JNK signaling 1998,14:33-38.

and

morphogenesis

in Drosophila.

transduction by the c-Jun to development Curr

Trends

N-terminal Opin Cell

Han SJ, Choi KY, Brey FT, Lee WJ: Molecular cloning characterization of a Drosophila p38 mitogen-activated kinase. ‘I Biol Chem 1998, 273:369-374.

kinase

protein

Han ZS, Enslen H, Hu X, Meng X, Wu I, Barret T, Davis RJ, Ip YT: A conserved p38 mitogen-activated protein kinase pathway regulates Drosophila immunity gene expression. MO/ Cell Biol 1998,18:3527-3539.

23. Suzanne M, lrie K, Glise B, Agnes F, Mori E, Matsumoto K, Noselli S: The Drosophila p38 MAPK pathway is required during oogenesis for egg asymmetric development Genes Dev 1999, 13:1464-i 474. This paper provides the first genetic analysis of a p38 MAPK pathway in a metaxoan, and shows that Drosophila JNK and p38 stress pathways have distinct functions during development. In oogenesis, p38 controls the activity of the EGFR ligand, and thus the ERK pathway.

6. .

JA, Hartenstein V: The development New York: Springer; 1985.

8.

Martinez-Arias A: Development and patterning of the larval epidermis of Drosophila. In The Development of Drosophila Melanogaster: vol 1. Edited by Bate M, Martinez-Arias A. New Cold Spring Harbor Laboratory Press; 1993:517-608.

9.

Young PE, Richman AM, Ketchum Drosophila requires nonmuscle Genes Dev 1993, 7:29-41.

IO.

Glise B, Bourbon Drosophila Map movement. Cell

11.

of Drosophila

York:

AS, Kiehart DP: Morphogenesis myosin heavy chain function.

H, Noselli S: hemipterous kinase kinase, required 1995,83:451-461.

encodes for epithelial

a novel cell sheet

Riesgo-Escovar JR, Jenni M, Fritz A, Hafen E: The Drosophila Jun-Nterminal kinase is required for cell morphogenesis but not for DJun-dependent cell fate specification in the eye. Genes Dev 1996, 10:2759-2768. Sluss HK, Han Z, Barrett T, Goberdhan DCI, Wilson C, Davis RJ, Ip M: A JNK signal transduction pathway that mediates morphogenesis and an immune response in Drosophila. Genes Dev 1996, 10:2745-2758.

13.

Kockel L, Zeitlinger J, Staszewski LM, Mlodzik M, Bohmann D: Jun in Drosophila development: redundant and nonredundant functions and regulation by two MAPK signal transduction pathways. Genes Dev 1997, 11:1748-l 758. [Published erratum appears in Genes Dev 1998, 12:447.]

14.

Hou XS, Goldstein Jun amino-terminal Decapentaplegic regulating epithelial 11:1728-l 737.

15.

16.

Glise B, Noselli Decapentaplegic morphogenesis.

S: Coupling of Jun amino-terminal signaling pathways in Drosophila Genes Dev 1997,ll :1738-l 747.

kinase

1 7.

Sluss HK, Davis RJ: Embryonic morphogenesis signaling pathway mediated by JNK targets the transcription factor and the TGF-fl homologue decapentaplegic. J Ce// Biochem 1997, 67:1-12. Riesgo-Escovar DJun during

JR, Hafen E, Common Drosophila development

25.

Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A, de la Pompa JL, Ferrick D, Hum B, lscove N et a/.: Early lethality, functional NF-KS activation, and increased sensitivity to TNF-induced cell death in TRAFZ-deficient mice. immunity 1997, 7:715-725.

26.

Hall A: Rho 279:509-514.

27.

Van Aelst networks.

28.

Harden N, Loh HY, Chia the small GTP-bindina structures and inhibits Drosophile. Development

GTPases

and

L, D’Susza-Schorey Genes Dev 1997,l

the actin

cytoskeleton.

Science

C: Rho GTPases I :2295-2322.

W, Lim L: A dominant orotein Rat disruots developmental cell 1995, 121:903-914.

and

1998,

signaling

inhibitory version cvtoskeletal shape changes in

of

Harden N, Rices M, Ong YM, Chia W, Lim L: Participation of small GTPases in dorsal closure of the Drosophila embryo: distinct roles for Rho subfamily proteins in epithelial morphogenesis. J Cell Sci 1999, 112:273-284. This study presents a genetic gain-of-function approach to try to determine the respective role of the Drosophila small GTPases Dracl , Dcdc42 and DrhoA during dorsal closure (see also [30’]). It reinforces the notion that each molecule plays specific functions in cytoskeletal assembly and dynamics but also suggests localized activities along the antero-posterior and dorso-ventral axes. 30. .

See 31.

Aop

Rices MG, Harden N, Sem KP, Lim L, Chia W: Dcdc42 acts in TGF-j3 signaling during Drosophila morphogenesis: distinct roles for the Dracl/JNK and Dcdc42/TGF-p cascades in cytoskeletal regulation. J Cell Sci 1999, 112:1225-l 235. annotation [29*]. Strutt DI, Weber U, Mlodzik M: The role of RhoA and Frizzled signalling. Nature 1997, 387:292-?95.

in tissue

polarity

32. .

and

and distinct roles of DFos Science 1997, 278:669-672.

Harden N, Lee J, Loh HY, Ong YM, Tan I, Leung T, Manser E, Lim L: A Drosophila homolog of the Rat- and Cdc42-activated serine/threonine kinase PAK is a potential focal adhesion and focal complex protein that colocalizes with dynamic actin structures. MO/ Cell Biol 1996, 16:1896-l 908.

Liu H, Su YC, Becker E, Treisman J, Skolnik EY: A Drosophila TNF receotor-associated factor (TRAF) binds the ste20 kinase misshapen and activates jun kinase. Curr Biol 1999, 9:101-104. The authors here identify the first Drosophila TRAFs, DTRAFl and DTRAFP, and show that DTRAFl, but not DTRAFP, binds and activates Misshapen (see [22-l) in cell cultures. They further show that the mammalian homdlog of Misshapen, NIK, also associates with TRAFs, suggesting a conserved link between TRAFs and StePO kinases.

JUN

Martin-Blanc0 E, Gampel A, Ring J, Virdee K, Kirov N, Tolkovsky AM, Martinez-Arias A: puckeredencodes a phosphatase that mediates a feedback loop regulating INK activity during dorsal closure in Drosophila. Genes Dev 1998, 12:557-570. This paper reports the cloning of the first MAPK phosphatase in Drosophila, puckered, and shows its specific role in the JNK pathway and dorsal closure (see also [16]), thus providing a molecular basis for a negative feedback loop in the control of JNK signaling. 33.

18.

in

29. .

ES, Perrimon N: Drosophila Jun relays the kinase signal transduction pathway to the signal transduction pathway in cell sheet movement. Genes Dev 1997,

Riesgo-Escovar JR, Hafen E: Drosophila Jun kinase regulates expression of decapentaplegic via the ETS-domain protein and the AP-1 transcription factor DJun during dorsal closure. Genes Dev 1997,11:1717-1727.

Yano DD. Kuan CY. Whitmarsh AJ. Rincon M. Zhena TS. Davis RJ. Rakyc P, Flavell RAI Absence of excitotoxicify-ind&ed’apoptosis the hippocampus of mice lacking the Jnk3 gene. Nature 1997, 389:865-870.

24. .

in

12.

Nat/

Su YC, Treisman JE, Skolnik EY: The Drosophila SteSO-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway. Genes Dev 1998,12:2371-2380. This paper shows the first genetic evidence that a Drosophila Ste20-related kinase, Misshapen, acts upstream of DJNKKlHEP during dorsal closure. Misshapen and its mammalian homolog, NIK, require the small GTPase Rat to activate the JNK pathway in cell cultures but, unlike other StePO-like mechanisms, Misshapen does not bind activated Rat directly, suggesting alternative mechanisms.

and

Campos-Ortega melanogaster.

HT, Xu J, Davis RJ, of the MKK4 gene causes c-Jun NH2-terminal kinase transcriptional activity. froc

D:

22. .

Biol

7.

J, Kockel L, Peverali FA, Jackson DB, Mlodzik M, Bohmann dorsal closure and loss of epidermal decapentaplegic in Drosophila fos mutants. EM60 J 1997,16:7393-7401.

and

Ring JM, Martinez Arias A: puckered, a gene involved specific cell differentiation in the dorsal epidermis Drosophila larva. Dev 1993, (Suppl):251-259.

in positionof the

Roles

34.

of the

JNK

signaling

Miyamoto H, Nihonmatsu I, Kondo S, Ueda R, Togashi S, Hirata K, lkegami Y, Yamamoto D: canoe encodes a novel protein containing a GlgWDhr motif and functions with Notch and scabrous in common developmental pathways in Drosophila. Genes Dev 1995, 9:612-625.

52.

Takahashi K, Matsuo T, Katsube T, Ueda R, Yamamoto D: Direct binding between two PDZ domain proteins Canoe and ZO-1 and their roles in regulation of the jun N-terminal kinase pathway in Drosophila morphogenesis. Mech . Dev 1998, 78:97-l 11. --This paper present a detalled analysis ot the InteractIon between two PULdomain proteins, Canoe and the Drosophila 20-l homolog. Canoe modulates the activity of the JNK pathway and co-localizes with 20-l at the adherens junctions, providing a link between cytoskeletal organization, cell adhesion and the process of dorsal closure. Craven SE, Bredt DS: PDZ proteins pathways. Cell 1998, 93:495-498.

organize

37.

Kiyokawa E, Hashimoto Y, Kobayashi S, Sugimura H, Kurata T, Matsuda M: Activation of Rad by a Crk SHB-binding protein, DOCK1 80. Genes Dev 1998,12:3331-3336.

38.

Wu YC, Horvitz protein CED-5 392:50 l-504.

39.

Erickson MR, Galletta BJ, Abmayr SM: Drosophila encodes a conserved protein that is essential dorsal closure, and cytoskeletal organization. 138:589-603.

HR: C. elegans phagocytosis is similar to human DOCK1

synaptic

signaling

and cell-migration 80. Nature 1998,

42.

43.

44.

of lethal(l)dislarge-I: melanogaster.

Dev

a &o/1988,

Fehon RG, Dawson IA, Artavanis-Tsakonas SA: Drosophila homologue of membrane-skeleton protein 41 is associated septate junctions and is encoded by the coracle gene. Development 1994, 120:545-557. Lamb RS, Ward member of the functions in the embryonic and 9:3505-3519.

Baumgartner S, Littleton JT, Broadie K, Bhat MA, Harbecke R, Lengyel JA, Chiquet-Ehrismann R, Prokop A, Bellen HJ: A Drosophila neurexin is required for septate junction and blood-nerve barrier formation and function. Cell 1996,87:1059-l 068. Hough CD, Woods DF, Park S, Bryant PJ: Organizing a functional junctional complex requires specific domains of the Drosophila MAGUK Discs large. Genes Dev 1997,11:3242-3253.

46.

Ward RE, Lamb RS, Fehon RG: A conserved functional domain of Drosophile coracle is required for localization at the septate junction and has membrane-organizing activity. J Cell Biol 1998, 14011463-l 473. Marfatia SM, Cabral JH, Lin L, Hough C, Bryant PJ, Stolz L, Chishti AH: Modular organization of the PDZ domains in the human discs-large protein suggests a mechanism for coupling PDZ domain-binding proteins to ATP and the membrane cytoskeleton. J Cell Biol 1996, 135:753-766.

Trinkaus JP: In Cells into Organs - The forces That Shape the Embryo. Edited by Clement L. Englewood Cliffs, New Jersey: Market and Prentice-Hall, Inc.; 1969.

57.

Williams-Masson EM, Malik AN, Hardin J: An actin-mediated step mechanism is required for ventral enclosure of the C. elegans hypodermis. Development 1997, 124:2889-2901.

58.

Martin Science

59.

Agnes F, Noselli S: Dorsal closure in Drosophila: a genetic for wound healing? C R Acad Sci 1111999, 322:5-l 3.

60.

Luo L, Liao YJ, Jan LY, Jan YN: Distinct morphogenetic functions of similar small GTPases: Drosophila Dracl is involved in axonal outgrowth and myoblast fusion. Genes Dev 1994, 8:1787-l 802

61.

Affolter M, Nellen D, Nussbaumer for the receptor serine/threonine functions of TGF p homologs Development 1994,120:3105-31

62.

Nellen D, Affolter M, Basler K: Receptor implicated in the control of Drosophile decapentaplegic. Cell 1994, 78:225-237.

Adler PN: The genetic control Bioessays 1992, 14~735.741.

50.

Shulman JM, Perrimon developmental control 14:452-458.

51.

Vinson CR, Conover S, Adler PN: A Drosophila encodes a protein containing seven potential domains. Nature 1989, 338:263-264.

of tissue

polarity

and 1998,

tissue polarity transmembrane

the

aiming

for perfect

skin

two-

regeneration. model

U, Basler K: Multiple requirements kinase thick veins reveal novel during Drosophila embryogenesis. 17. serineithreonine body pattern

kinases by

Penton A, Chen Y, Staehling-Hampton K, Wrana JL, Attisano L, Szidonya J, Cassill JA, Massague J, Hoffmann FM: Identification of two bone morphogenetic protein type I receptors in Drosophila and evidence that Brk25D is a decapentaplegic receptor. Cell 1994,78:239-250.

64.

Brummel TJ. Twomblv V. Maraues Attisano L, hassag& JI O’C&nor Characterization and relationship the saxophone and thick veins 78:251-561.

G. Wrana JL. Newfeld MB, Gelbait WM: of Dpp receptors genes in Drosophila.

SJ. encoded by Cell 1994,

Ruberte E. Martv T. Nellen D. Affolter M. Basler K: An absolute requirement fo; b&h the type II and type I receptors, punt thick veins, for dpp signaling in viva. Cell 1995, 80:889-897.

and

Letsou A, Arora K, Wrana JL, Simin K, Twombly V, Jamal J, Staehling Hampton K, Hoffmann FM, Gelbart WM, Massague J et a/.: Drosophila Dpp signaling is mediated by the punt gene product: dual llgand-binding type II receptor of the TGF p receptor family. Cell 1995,80:899-908.

67.

Simin K, Bates EA, Horner MA, Letsou A: Genetic analysis of punt, type II Dpp receptor that functions throughout the Drosophila melanogaster life cycle. Genetics 1998, 148:801-813.

68.

Arora K, Dai H, Kazuko SG, Jamal J, O’Connor MB, Letsou A, Warrior R: The Drosophila schnurri gene acts in the Dpp/TGF beta signaling pathway and encodes a transcription factor homologous to the human MBP family. Cell 1995, El:781 -790.

69.

Grieder required

in Drosophila.

N, Axelrod JD: Frizzled signaling of cell polarity. Trends Genet

P: Wound healing: 1997, 276:75-81.

A, Sussman DJ, pathways. in mammalian

63.

66.

49.

Eaton S, Wepf R, Simons K: Roles for Racl and Cdc42 in planar polarization and hair outgrowth in the wing of Drosophila. J Cell Biol 1996, 135:1277-l 289.

56.

65.

Marfatia SM, Leu RA, Branton D, Chishti AH: Identification of the protein 4-1 binding interface on glycophorin C and ~55, a homologue of the Drosophile discs-large tumor suppressor protein. J Viol Chem 1995, 270:715-719.

471

Li L, Yuan H, Xie W, Mao J, Caruso AM, McMahon Wu D: Dishevelled proteins lead to two signaling Regulation of LEF-1 and c-Jun N-terminal kinase cells. J Biol Chem 1999, 274:129-l 34.

in

48.

Agnes

55.

a

45.

47.

and

Axelrod JD, Miller JR, Shulman, JM, Moon RT, Perrimon N: Differential recruitment of dishevelled provides signaling specificity in the planar cell polarity and wingless signaling pathways. Genes Dev 1998, 12:261 O-2622. The authors show that transduction of the planar polarity and wingless signaling Dathwavs reauire different domains of the Dishevelled orotein in Drosibhila. Thk authbrs further show that the DEP domain of Discevelled is required specifically for planar polarity and the recruitment of Dishevelled to the membrane by the Frizzled receptor in an heterologous system. This recruitment may result in the asymmetric relocalization of Dishevelled to the membrane and the establishment of planar polarity.

with

RE, Schweizer L, Fehon RG: Drosophila coracle, protein 41 superfamily, has essential structural septate junctions and developmental functions adult epithelial cells. MO/ B/o/ Cell 1998,

Noselli

54. .

myoblast city for myoblast fusion, J Cell Biol 1997,

Nolan KM, Barrett K, Lu Y, Hu KQ, Vincent S, Settleman J: Myoblast city, the Drosophila homolog of DOCK1 80/CED-5, is required in a Rat signaling pathway utilized for multiple developmental processes. Genes Dev 1998,12:3337-3342. ..I .., This paper prOVldt?S genetlc and blocnemlcal evidence ot a specitlc and upstream role of the Drosophila DOCK1 80/CED-5 homolog mbc in mediating Racl functions in the eye and dorsal closure. Perrimon N: The maternal effect recessive oncogene of Drosophila 127:392-407.

morphogenesis

Boutros M, Paricio N, Strutt DI, Mlodzik M: Dishevelled activates INK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell 1998, 94: 109-l 18. This paper uses loss- and gain-of-function genetic interactions to demonstrate a role of the JNK pathway downstream of frizzled/dishevelled in the control of planar polarity in the eye. It also shows that activation of jun phosphorylation in cell cultures depends on the DEP domain of dishev-

40. .

41.

in Drosophila

53. .

35. .

36.

pathway

locus

NC, Nellen D, Burke R, Basler for Drosophile Dpp signaling

K, Affolter M: Schnurri and encodes a zinc

is finger

a

a

472

Pattern

formation

protein similar to the Cell 1995,81:791-800. 70.

71.

72.

Staehling-Hampton protein related PRDlI/MBPI/HIV-EPI 1995,121:3393-3403.

and

developmental

mammalian

transcription

mechanisms

factor

PRDII-BFI.

functions Drosophila

K, Laughon AS, Hoffmann FM: A Drosophila to the human zinc finger transcription factor is required for dpp signaling. Developmenf

73.

MacKrell AJ, Blumberg B, Haynes SR, Fessler JH: The lethal myospheroid gene of Drosophila encodes a membrane protein homologous to vertebrate integrin beta subunits. froc Nat/ Acad SC; USA 1988, 85:2833-2637. Stark KA, Yee GH, Roote CE, A novel alpha integrin subunit

Williams EL, Zusman S, Hynes associates with BPS and

RO:

74.

75.

in tissue morphogenesis development. Development

and

movement during 1997, 124:4583-4594.

Manfruelli P, Arquier N, Hanratty WP, Semeriva M: The tumor suppressor gene, lethal(Z)gi larvae (1 (Z)gl), is required cell shape change of epithelial cells during Drosophila development. Development 1996, 122:2283-2294. Borchiellini collagen 58:179-191.

C, Coulon J, Le Parco Y: The function during Drosophila muscle development.

of type Mech

IV Dev

for

1996,

Blake KJ, Myette G, Jack J: The products of ribbon and raw are necessary for proper cell shape and cellular localization of nonmuscle myosin in Drosophila. Dev Biol 1998, 203:177-l 88.