Inhibition of patterned cell shape change and cell invasion by Discs large during Drosophila oogenesis

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.

Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis

“…To determine which junctions suppress tumor invasion, we took advantage of the previous observation that loss of Dlg causes follicle cells to overproliferate, change polarity, delaminate from the native epithelium, and invade between germ cells, all characteristics of invasive tumor cells in humans and other vertebrates (Goode and Perrimon, 1997;Goode et al, 2005). The invariant movement of dlg tumors toward the oocyte resembles invasion by BCs (Figs.…”

“…The invariant movement of dlg tumors toward the oocyte resembles invasion by BCs (Figs. 1A, 2A,D), but dlg tumor cells start invading early in oogenesis and do not adopt a BC fate (Goode and Perrimon, 1997). We used both tumor invasion and BC migration as assays to determine which epithelial junctions are crucial for suppressing invasion in vivo.…”

“…1E) (Goode et al, 2005). Second, some dlg alleles only cause overproliferation and multilayering of the epithelium, while others also cause invasion (Goode and Perrimon, 1997). Third, although Nrg loss typically results in small, 2-to 3-cell clusters, they nonetheless invade between germ cells (Fig.…”

“…Discs-large (Dlg), a BLJ scaffolding protein that includes PDZ and other protein-interaction domains, directly suppresses epithelial invasion. Decrease or loss of Dlg results in both faster BC migration (Szafranski and Goode, 2004) and development of invasive tumors during early oogenesis (Goode and Perrimon, 1997;Goode et al, 2005). We have recently found that two transmembrane cell adhesion molecules of the immunoglobulin superfamily, Fasciclin-2 (Fas2) and Neuroglian (Nrg), are also specifically localized to the BLJ (Szafranski and Goode, 2004;Wei et al, 2004).…”

Hsp60C is required in follicle as well as germline cells during oogenesis in Drosophila melanogaster

“…The antibodies used for immunostaining were: anti-Fas-III (1:10; Patel et al, 1987), anti-Gurken (1:30; Queenan et al, 1999), anti-Dlg (1:20;Goode and Perrimon, 1997), antiHts-RC (1:1; Robinson et al, 1994), anti-␣-spectrin (1:50;Dubreuil et al, 1987), anti-DE-Cadherin (1:20;Oda et al, 1997), all obtained from Developmental Studies Hybridoma Bank (USA); the other antibodies were Mouse monoclonal Anti-Phosphotyrosine (1:100, Santa Cruz, CA), monoclonal anti-␣-tubulin-FITC Conjugate (DM1A, 1:250, SIGMA), and rabbit polyclonal anti-Hsp60 (SPA 805, 1:100, Stressgen, Canada).…”