Tightly controlled basement membrane (BM) remodeling is thought to be essential for animal development and adult life. However, the full picture of BM dynamics and their functional importance remains largely unknown, especially in mammals, due to the lack of effective tools for visualizing BM dynamics in real time. Here, we established knock-in mice expressing fluorescently tagged collagen type IV alpha 2 chain (COL4A2) and a long-term 3D live-imaging system to capture BM dynamics. Imaging of growing hair follicles revealed that BM dynamics show regional BM turnover and elongation, which tightly control epithelial progenitor proliferation. Exposure to a matrix metalloproteinase inhibitor disrupts BM dynamics, causes a disproportionate shape of the hair follicle, and alters cellular division orientation. These results suggest that BM dynamics are tightly controlled in time and space during mammalian development and play essential roles in organogenesis by controlling the proliferation and fate of progenitor cells.
Duligengaowa Wuergezhen, Eleonore Gindroz, Ritsuko Morita, Kei Hashimoto, Takaya Abe, Hiroshi Kiyonari, Hironobu Fujiwara (2025) An eGFP-Col4a2 mouse model reveals basement membrane dynamics underlying hair follicle morphogenesis., The Journal of cell biology, Volume 224, Number 2
Published in 2025 Feb 3 (Electronic publication in Dec. 10, 2024, midnight )
(Abstract) Precisely controlled remodeling of the basement membrane (BM) is crucial for morphogenesis, but its molecular and tissue-level dynamics, underlying mechanisms, and functional significance in mammals remain largely unknown due to limited visualization tools. We developed mouse lines in which the endogenous collagen IV gene (Col4a2) was fused with a fluorescent tag. Through live imaging of developing hair follicles, we reveal a spatial gradient in the turnover rate of COL4A2 that is closely coupled with both the BM expansion rate and the proliferation rate of epithelial progenitors. Epithelial progenitors are displaced with directionally expanding BMs but do not actively migrate on stationary BM. The addition of a matrix metalloproteinase inhibitor delays COL4A2 turnover, restrains BM expansion, and increases perpendicular divisions of epithelial progenitors, altering hair follicle morphology. Our findings highlight the spatially distinct dynamics of BM and their key roles in orchestrating progenitor cell behavior and organ shape during development.(MeSH Terms)