Basolateral Junctions Utilize Warts Signaling to Control Epithelial-Mesenchymal Transition and Proliferation Crucial For Migration and Invasion of Drosophila Ovarian Epithelial Cells

Abstract

Fasciclin2 (Fas2) and Discslarge (Dlg) localize to the basolateral junction (BLJ) of Drosophila follicle epithelial cells and inhibit their proliferation and invasion. To identify a BLJ signaling pathway we completed a genomewide screen for mutants that enhance dlg tumorigenesis. We identified two genes that encode known BLJ scaffolding proteins, lethal giant larvae (lgl) and scribble (scrib), and several not previously associated with BLJ function, including warts (wts) and roughened eye (roe), which encode a serine-threonine kinase and a transcription factor, respectively. Like scrib, wts and roe also enhance Fas2 and lgl tumorigenesis. Further, scrib, wts, and roe block border cell migration, and cause noninvasive tumors that resemble dlg partial loss of function, suggesting that the BLJ utilizes Wts signaling to repress EMT and proliferation, but not motility. Apicolateral junction proteins Fat (Ft), Expanded (Ex), and Merlin (Mer) either are not involved in these processes, or have highly spatio-temporally restricted roles, diminishing their significance as upstream inputs to Wts in follicle cells. This is further indicated in that Wts targets, CyclinE and DIAP1, are elevated in Fas2, dlg, lgl, wts, and roe cells, but not Fat, ex, or mer cells. Thus, the BLJ appears to regulate epithelial polarity and dynamics not only as a localized scaffold, but also by communicating signals to the nucleus. Wts may be regulated by distinct junction inputs depending on developmental context.

Requirements of Lgl in cell differentiation and motility during Drosophila ovarian follicular epithelium morphogenesis

“…43 It has been reported that Lgl collaborates with Dlg and Fasciclin 2 to regulate border cell delamination and migration of border cell cluster. 10,19 Consistent with this report, we found that loss-offunction mutations in lgl lead to a failure of border cell delamination from the anterior epithelium, as demonstrated by blocked movement of the border cells in the stage 10 mosaic egg chambers harboring the anterior clones homozygous for lgl 4w3 (Fig. 3B) Fig.…”

“…32 Most recently, we showed that scrib genetically interacts with dlg in posterior patterning of ovarian follicular epithelium. 37 Considering that lgl, dlg and scrib work in concert to regulate cell polarity and proliferation in the epithelial tissues, 10,18,19,22,23,[38][39][40][41][42] we intended to determine whether these three genes act in a common pathway to function in PFC specification and differentiation. To address this issue, we tested for genetic interactions among the three mutations and detected strong interactions of lgl with dlg and scrib in the examined process.…”

“…10,18,19,[22][23][24][25][26] We and others have shown that lgl/dlg/scrib are required for a number of developmental controls during oogenesis. 10,[18][19][20]22,23,[27][28][29][30][31][32][33][34][35][36] In particular, we have identified Lgl as an essential regulator in PFC specification and differentiation, and a role of dlg/scrib in both anterior and posterior patterning of the follicular epithelium. 32,37 In this paper, we show that lgl genetically interacts with dlg/scrib in PFC fate induction, suggesting a common regulatory pathway in this process.…”

“…[5][6][7][8][9][10][11][12][13][14] In addition, the apico-basal polarity and DE-Cadherin based adhesion are crucial for the integrity of border cell cluster during its morphogenetic movement. 6,15,16 As developmental cell migration and pathological cell invasion involve common cellular and biological processes, 3,10,[17][18][19][20][21] further investigation of this model system will contribute to unraveling the molecular mechanisms underlying cancer invasion and metastasis. The Drosophila nTSGs lgl, dlg and scrib cooperatively function in multiple biological processes, including cell polarity and proliferation control in epithelial tissues, tumor cell invasion and asymmetric division of neuroblasts.…”

Oocyte destruction is activated during viral infection

“…One such gene, discs large (dlg), appears to control the polarity of the follicle cell layer (Assemat et al, 2008;Zhao et al, 2008) by participating in junctional complexes between epithelial cells. When fed RAP, flies heterozygous for both a dlg null allele and, separately, a temperature-sensitive allele, were found to lay significant numbers of embryos while wild-type flies laid zero embryos .…”