Integrin Adhesions Suppress Syncytium Formation in the Drosophila Larval Epidermis

Abstract

Summary Integrins are critical for barrier epithelial architecture. Integrin loss in vertebrate skin leads to blistering and wound healing defects. However, how Integrins and associated proteins maintain the regular morphology of epithelia is not well understood. We found that targeted knockdown of the integrin focal adhesion (FA) complex components βIntegrin, PINCH, and Integrin-linked kinase (ILK), caused formation of multinucleate epidermal cells within the Drosophila larval epidermis. This phenotype was specific to the Integrin FA complex and not due to secondary effects on polarity or junctional structures. The multinucleate cells resembled the syncytia caused by physical wounding. Live imaging of wound-induced syncytium formation in the pupal epidermis suggested direct membrane breakdown leading to cell-cell fusion and consequent mixing of cytoplasmic contents. Activation of Jun N-terminal kinase (JNK) signaling, which occurs upon wounding, also correlated with syncytium formation induced by PINCH knockdown. Further, ectopic JNK activation directly caused epidermal syncytium formation. No mode of syncytium formation including that induced by wounding, genetic loss-of FA-proteins, or local JNK hyperactivation, involved misregulation of mitosis or apoptosis. Finally, the mechanism of epidermal syncytium formation following JNK hyperactivation and wounding appeared to be direct disassembly of FA complexes. In conclusion, the loss of function phenotype of Integrin FA components in the larval epidermis resembles a wound. Integrin FA loss in mouse and human skin also causes a wound-like appearance. Our results reveal a novel and unexpected role for proper Integrin-based adhesion in suppressing larval epidermal cell-cell fusion– a role that may be conserved in other epithelia.

Integrin suppresses neurogenesis and regulates brain tissue assembly in planarian regeneration

“…These observations indicate that patterning and the ability of progenitors to undergo differentiation are likely to be insufficient for appropriate blastema assembly. Integrins can control cell proliferation, survival, migration and adhesion to participate in stem cell/niche interactions, wound healing and formation of tissue barriers among other outputs (Tanentzapf et al, 2007;Goulas et al, 2012;Maartens and Brown, 2015;Wang et al, 2015). Our results suggest that integrins have a prominent role in the organization of regenerative tissue.…”

Spatiotemporal regulation of cell fusion by JNK and JAK/STAT signaling during Drosophila wound healing

“…whether JNK induces cell fusion only by inhibiting JAK/STAT signaling, or alternatively, whether JNK directly controls the fusion process in addition to suppressing JAK/ STAT signaling. Because JNK activation, but not loss of JAK/STAT signaling, induced cell fusion in the absence of wounding (Wang et al, 2015; data not shown), the former hypothesis must be rejected. To verify this idea in the context of wound healing, we blocked JAK/STAT signaling by overexpressing dome DN and simultaneously blocked JNK by overexpressing bsk DN .…”

“…We tested whether JAK/STAT pathway activation could suppress JNK-induced cell fusion by overexpressing constitutively active hep (hep CA ) and hop together in a patch of dorsal epidermal cells (Wang et al, 2015). In control groups, hop overexpression did not induce cell fusion (Fig.…”

“…It has been reported recently that the focal adhesion complex involving integrin protein suppresses cell fusion in the larval epidermis (Wang et al, 2015). Interestingly, JAK/ STAT pathway activation is known to increase βPS integrin (also known as Myospheroid) protein expression in somatic stem cells of the testis (Issigonis et al, 2009).…”

“…Here, cell fusion was proposed to help clear cellular debris (Galko and Krasnow, 2004) and, along with cell migration and growth, contribute to wound closure (Losick et al, 2013). Cell fusion is promoted by JNK pathway (JNK is also known as Basket in flies) activation, which appears to be mediated by disassembly of the integrin focal adhesion complex (Wang et al, 2015). Cell fusion is also under the control of the Hippo pathway transcription factor Yki (Losick et al, 2013).…”