Multiple functions of the scaffold protein Discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster

Abstract

Background : Scaffold proteins support a variety of key processes during animal development. Mutant mouse for the MAGUK protein Discs large 5 (Dlg5) presents a general growth impairment and moderate morphogenetic defects. Results : Here, we generated null mutants for Drosophila Dlg5 and show that it owns similar functions in growth and epithelial architecture. Dlg5 is required for growth at a cell autonomous level in several tissues and at the organism level, affecting cell size and proliferation. Our results are consistent with Dlg5 modulating hippo pathway in the wing disc, including the impact on cell size, a defect that is reproduced by the loss of yorkie. However, other observations indicate that Dlg5 regulates growth by at least another way that may involve Myc protein but nor PI3K neither TOR pathways. Moreover, epithelia cells mutant for Dlg5 also show a reduction of apical domain determinants, though not sufficient to induce a complete loss of cell polarity. Dlg5 is also essential, in the same cells, for the presence at Adherens junctions of N-Cadherin, but not E-Cadherin. Genetic analyses indicate that junction and polarity defects are independent. Conclusions : Together our data show that Dlg5 own several conserved functions that are independent of each other in regulating growth, cell polarity and cell adhesion. Moreover, they reveal a differential regulation of E-cadherin and N-cadherin apical localization.

Transcellular chaperone signaling is an intercellular stress-response distinct from the HSF-1 mediated HSR

“…Our data shows that TXT-1 and CEH-58 genetically interact as part of an intra-cellular signaling cue in the C. elegans bodywall muscle, corroborating a previous yeast-two-hybrid study that demonstrated direct interaction between both proteins (Lenfant et al, 2010). Although our study is the first to note an association of TXT-1 with the heat stress response in C. elegans, its closest human orthologue, DLG5, is a membrane associated guanylate cyclase that is part of the Hippo pathway (Venugopal et al, 2020;Zhu et al, 2016) and is involved in the cellular response to heat stress (Luo et al, 2020). Extracellular peptides may be important contributors of organismal proteostasis that enable intercellular signaling (Melo and Ruvkun, 2012).…”

Dlg5 and Cadherins are key to peripheral glia integrity

“…The loss of Dlg5 disrupted the distribution of Arm (Liu et al, 2014b) (beta-catenin) in border cells (Luo et al, 2019) and E-Cadherin in follicular cells (Luo et al, 2016), yet had no effect on the distribution of Dlg1 or the SJ protein Neuroglian (Luo et al, 2019). In wing discs, Dlg5 mutants have a reduction of apical domain determinants but not a loss of cell polarity and a very specific defect in the recruitment of N-Cadherin to adherens junctions but not E-Cadherin (Venugopal et al, 2020). Our results shown that in the SPG, Dlg5 was not found associated with any junctional complex except with Ncad and Ecad and was excluded from the SJ.…”

“…Dlg5 performs multiple independent functions in both mammals and Drosophila. Dlg5 has a wide range of functions including regulation of cell proliferation, polarity, growth, and trafficking of junctional complexes and these functions are are highly context specific (Kwan et al, 2016; Liu et al, 2017; Venugopal et al, 2020).…”

“…In Drosophila muscle development, Dlg5 acts indirectly on Hippo signaling as a regulator of the STRIPAK phosphatase, which negatively regulates Hippo to enable post-mitotic muscle growth (Kaya-Copur et al, 2021). In the Drosophila eye and imaginal wing epithelia, loss of Dlg5 leads to reduced size of these organs, and is thought to act as a negative regulator of Hippo signalling (Kwan et al, 2016; Venugopal et al, 2020), meaning that loss of Dlg5 leads to increased Hippo signaling and decreased Yorkie activation. In the SPG a decrease in Yorkie causes abnormal endoreplication, aberrant DNA ploidy, defective septate junctions and BBB disruption (Li et al, 2017).…”