Argos induces programmed cell death in the developing Drosophila eye by inhibition of the Ras pathway

Sawamoto, Kazunobu; Taguchi, Akiko; Hirota, Yuki; Yamada, Chiharu; Jin, Minghao; Okano, Hideyuki

doi:10.1038/sj.cdd.4400342

Cited by 52 publications

(38 citation statements)

References 34 publications

(67 reference statements)

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“…GMR-dRet MEN2A pupal eye tissue showed indistinguishable defects (data not shown). Similar pupal eye phenotypes have been reported for Ras85D V12 overexpression (Sawamoto et al 1998). Histological sections of adult GMR-dRet MEN2B retinae showed variable numbers of photoreceptors, poorly spaced ommatidia, and large vacuolated spaces ( Figure 4D).…”

Section: Men2asupporting

confidence: 55%

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

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et al. 2005

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Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that Ret MEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which Ret MEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for Ret MEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRet MEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRet MEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRet MEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRet MEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis. D URING development, receptor tyrosine kinases (RTKs) integrate extracellular signals to influence cellular processes such as growth and differentiation. Signaling through RTKs requires ligand-induced oligomerization to direct tyrosine autophosphorylation; autophosphorylation both stimulates catalytic activity and creates phospho-tyrosine docking sites for cytoplasmic proteins that activate intracellular signaling pathways. To date, mutations in more than half of all RTKs have been implicated in human cancer (reviewed in Blume-Jensen and Hunter 2001). These mutations commonly function by relieving RTK regulatory constraints, leading to inappropriate kinase activity and hyperactivation of downstream pathways. These events promote oncogenic transformation by driving aberrant cellular growth, proliferation, and survival. Still, tumorigenesis requires mutations in multiple loci: along with dominant mutations in oncogenes such as RTKs, tumorigenesis also requires loss-of-function mutations in tumor suppressors. The relationship between oncogenic tyrosine kinases and tumor suppressors, and the extent to which mutations in each cooperate to direct oncogenic growth, is not well understood.The Ret RTK plays an essential role in both development and oncogenesis. During embryogenesis, Ret is required for development of the sympathetic and enteric nervous systems, the neural crest, and the excretory system (Schuchardt et al. 1994;Durbec et al. 1996;Enomoto et al. 2001). The extracellular portion of Ret contains cysteine repeats and a cadherinlike domain. The intracellular portion of Ret contains a tyrosine kinase catalytic domain and multiple tyrosine autophosphorylation sites. Four activating ligands have been identified: GDNF, Neurturin, Persephin, and Artemin all activate Ret through the GPI-linked co-

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Section: Men2asupporting

confidence: 55%

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

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et al. 2005

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“…Indeed, cone and PP cells express an EGFR ligand called Spitz at the time of IPC apoptosis, consistent with this model [26]. Furthermore, loss of EGFR activity results in ectopic cell death [27,28]. EGFRdependent signaling in IPCs inhibits the Head Involution Defective (Hid) protein, an inhibitor of DIAP, which is itself an inhibitor of the apoptotic caspase pathway [29].…”

Section: Culling Of the Patternmentioning

confidence: 71%

“…Argos, a secreted repressor of EGFR signaling, is expressed in cone, SP, and TP cells [30]. Overexpression of Argos results in enhanced apoptosis [28,30,31]. One attractive model is that Argos diffuses from cone cells and limits the influence of Spitz to promote survival to only those IPCs closest to the Spitz source.…”

Section: Culling Of the Patternmentioning

confidence: 99%

Pattern formation in the Drosophila eye

Carthew

2007

Current Opinion in Genetics & Development

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The insect compound eye is one of the most precise and highly ordered patterns in the living world. It develops from an unpatterned simple epithelium by a series of cell fate decisions and complex morphogenetic movements. In the first days of metamorphosis, this interplay is particularly noticeable. Recent insights have revealed how interactions between neighboring cells drive the process. Interaction between Delta on cone cells and Notch proteins on the surface of neighbors induces the first pigment cells to differentiate. The primary pigment cells then express a Nephrin protein, Hibris, that interacts with a different Nephrin, Roughest, on their neighbors. Heterophilic adhesion between Hibris and Roughest result in remodeling contacts between cells to favour their contact with the pigment cells. In conjunction, the primary pigment cells signal to neighbors through the EGF Receptor to survive rather than undergo apoptosis. This sorting and culling process results in a sculpted pattern with a precise number and position of cells that is repeated hundreds of times in each compound eye.

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“…In particular, the function of Ras1 in ommatidial development has been well documented (Wassarman and Therrien, 1997). It has been shown that the expression of a constitutively activated Ras1 (Ras1 G12V ) in developing eyes has several distinct eects on various developmental stages, i.e., transformation of non-neuronal cone cells into ectopic R7 cells (Fortini et al, 1992), induction of hyperplastic growth (Karim and Rubin, 1998) and inhibition of programmed cell death (Sawamoto et al, 1998;Miller and Cagan, 1998). These functions of Ras1 are likely to be mediated by one of the Ras eectors, D-raf/Raf.…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of constitutively activated Ral GTPase inhibits cell shape changes during Drosophila eye development

et al. 1999

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The small GTP-binding protein Ral is activated by RalGDS, one of the eector molecules for Ras. Active Ral binds to a GTPase activating protein for CDC42 and Rac. Although previous studies suggest a role for Ral in the regulation of CDC42 and Rac, which are involved in arranging the cytoskeleton, its in vivo function is largely unknown. To examine the eect of overexpressing Ral on development, transgenic Drosophila were generated that overexpress wild-type or mutated Ral during eye development. While wild-type Ral caused no developmental defects, expression of a constitutively activated protein resulted in a rough eye phenotype. Activated Ral did not aect cell fate determination in the larval eye discs but caused severe disruption of the ommatidial organization later in pupal development. Phalloidin staining showed that activated Ral perturbed the cytoskeletal structure and cell shape changes during pupal development. This phenotype is similar to that caused by RhoA overexpression. In addition, the phenotype was synergistically enhanced by the coexpression of RhoA. These results suggest that Ral functions to control the cytoskeletal structure required for cell shape changes during Drosophila development.

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Argos induces programmed cell death in the developing Drosophila eye by inhibition of the Ras pathway

Cited by 52 publications

References 34 publications

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

Pattern formation in the Drosophila eye

Ectopic expression of constitutively activated Ral GTPase inhibits cell shape changes during Drosophila eye development

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