Abstract
Tissue development demands precise control of cell proliferation and organization, which is achieved through multiple conserved signaling pathways and protein complexes in multicellular animals. Epithelia are a ubiquitous tissue type that provide diverse functions including physical protection, barrier formation, chemical exchange, and secretory activity. However, epithelial cells are also a common driver of tumorigenesis; thus, understanding the molecular mechanisms that control their growth dynamics is important in understanding not only developmental mechanisms but also disease. One prominent pathway that regulates epithelial growth is the conserved Hippo/Warts/Yorkie network. Hippo/Warts inactivation, or activating mutations in Yorkie that prevent its phosphorylation (e.g., YkiS168A), drive hyperplastic tissue growth. We recently reported that loss of Mushroom body defect (Mud), a microtubule-associated protein that contributes to mitotic spindle function, restricts YkiS168A-mediated growth in Drosophila imaginal wing disc epithelia. Here we show that Mud loss alters cell cycle progression and triggers apoptosis with accompanying Jun kinase (JNK) activation in YkiS168A-expressing discs. To identify additional molecular insights, we performed RNAseq and differential gene expression profiling. This analysis revealed that Mud knockdown in YkiS168A-expressing discs resulted in a significant downregulation in expression of core basement membrane (BM) and extracellular matrix (ECM) genes, including the type IV collagen gene viking. Furthermore, we found that YkiS168A-expressing discs accumulated increased collagen protein, which was reduced following Mud knockdown. Our results suggest that ECM/BM remodeling can limit untoward growth initiated by an important driver of tumor growth and highlight a potential regulatory link with cytoskeleton-associated genes.
Highlights
Tissue development requires proper assembly of three-dimensional shape and expansion to the correct final size
We recently found that knockdown of Mushroom body defect (Mud), a conserved microtubule (MT)-associated protein involved in mitotic spindle assembly and function, suppresses hyperplastic wing disc growth induced by expression of constitutively active YkiS168A [17], which is rendered insensitive to Warts phosphorylation in the key 14-3-3 binding motif [18]
YkiS168A expression induced a ~15-fold increase in wing disc size in late L3 stage larvae, which was significantly reduced by mudRNAi expression
Summary
Tissue development requires proper assembly of three-dimensional shape and expansion to the correct final size. Deciphering the genetic basis for these complex events and the underlying regulatory mechanisms involved are critical endeavors. Epithelial cells adopt distinct shapes and organizations that contribute to their diverse functions. Disruption of their discrete architectures can lead to tissue dysfunction and abnormal growth [1]. Epithelia are a common driver of tumorigenesis in many organs (e.g., carcinomas) and these tumors often arise following mutations in genes controlling growth and proliferation, as well as in those involved in polarity and junctional organization [2]. It is important to continue advancing our understanding of the complex dynamics of epithelial growth, including in model organism systems
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