ECM-Regulator timp Is Required for Stem Cell Niche Organization and Cyst Production in the Drosophila Ovary

Abstract

The extracellular matrix (ECM) is a pivotal component adult tissues and of many tissue-specific stem cell niches. It provides structural support and regulates niche signaling during tissue maintenance and regeneration. In many tissues, ECM remodeling depends on the regulation of MMP (matrix metalloproteinase) activity by inhibitory TIMP (tissue inhibitors of metalloproteinases) proteins. Here, we report that the only Drosophila timp gene is required for maintaining the normal organization and function of the germline stem cell niche in adult females. timp mutant ovaries show reduced levels of both Drosophila Collagen IV α chains. In addition, tissue stiffness and the cellular organization of the ovarian niche are affected in timp mutants. Finally, loss of timp impairs the ability of the germline stem cell niche to generate new cysts. Our results demonstrating a crucial role for timp in tissue organization and gamete production thus provide a link between the regulation of ECM metabolism and tissue homeostasis.

Variations in basement membrane mechanics are linked to epithelial morphogenesis

“…These results are in accordance with previous analyses showing that indentions of about one-third of the depth of the layer give the stiffness of that layer (Milani et al, 2011). In two studies showing AFM measurements of BM stiffness in follicles, the measured stiffness is ten times softer than in our analyses, but with a deeper indentation (200 nm) (Diaz de la Loza et al, 2017;Pearson et al, 2016). This is consistent with our observations that stiffness decreases as indentation depth increases.…”

Juvenile hormone and 20-hydroxyecdysone coordinately control the developmental timing of matrix metalloproteinase–induced fat body cell dissociation

“…Our previous work has demonstrated the collaborative functions of Mmp1 and Mmp2 in inducing fat body cell dissociation in Drosophila (2). timp mutant adults show autolyzed tissue in the abdominal cavity and inflated wings, a phenotype consistent with the role of timp in BM integrity and remodeling (33). The current study clarified the role of timp in inhibiting the enzy-matic activity of Mmps and thus, Mmp-induced fat body cell dissociation ( Fig.…”

“…S4). In mammals, Mmps activity in vivo is controlled at different levels, including the regulation by gene expression, the zymogens activation, and the inhibition of active enzymes by TIMPs (33,34). These studies unify the important inhibitory roles of timp/TIMP in regulating tissue remodeling in both Drosophila and mammals.…”

Minireview: Syndecans and their crucial roles during tissue regeneration

“…There are various type of progenitor cells in mammalian tissues including skin (epidermal stem cells) [83], blood vessel (vascular progenitor cells) [84], bone (bone marrow) [85], skeletal muscle (satellite cells) [86], and nerve (neural stem cells) [87], and they are involved in sustaining tissues by selfrenewal. In invertebrates, Drosophila also has adult stem cells in its intestine and ovary [88,89]. During selfrenewal of regenerative stem cells, Wnt-and Hedgehog (Hh) signaling play important roles in maintenance and differentiation of stem cells in mammalian tissue and Drosophila [90,91].…”