Ku Hui-Yu, Bilder David
Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, CA 94720.
Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2412161122. doi: 10.1073/pnas.2412161122. Epub 2025 May 13.
While paradigms for patterning of cell fates in development are well established, paradigms for patterning morphogenesis, particularly when organ shape is influenced by the extracellular matrix (ECM), are not. Morphogenesis of the egg chamber (follicle) depends on anterior-posterior distribution of basement membrane (BM) components such as Collagen IV (Col4), whose gradient creates tissue mechanical properties that specify the degree of elongation. Here, we show that the gradient is not regulated by Col4 transcription but instead relies on posttranscriptional mechanisms. The metalloprotease ADAMTS-A, expressed in a gradient inverse to that of Col4, limits Col4 deposition in the follicle center and manipulation of its levels can cause either organ hyper- or hypoelongation. We present evidence that ADAMTS-A acts within the secretory pathway, rather than extracellularly, to limit Col4 incorporation into the BM. High levels of ADAMTS-A in follicle termini are normally dispensable but suppress Col4 incorporation when transcription is elevated. Meanwhile, the terminally expressed metalloprotease Stall increases Col4 turnover in the posterior. Our data show how an organ can employ patterned expression of ECM proteases with intracellular as well as extracellular activity to specify BM properties that control shape.
虽然发育过程中细胞命运模式形成的范例已得到充分确立,但形态发生模式形成的范例,尤其是当器官形状受细胞外基质(ECM)影响时,却并非如此。卵室(卵泡)的形态发生取决于基底膜(BM)成分(如胶原蛋白IV(Col4))的前后分布,其梯度产生组织机械特性,从而决定伸长程度。在这里,我们表明该梯度不是由Col4转录调节的,而是依赖于转录后机制。金属蛋白酶ADAMTS-A以与Col4相反的梯度表达,限制Col4在卵泡中心的沉积,操纵其水平可导致器官过度伸长或伸长不足。我们提供的证据表明,ADAMTS-A在分泌途径内而非细胞外起作用,以限制Col4掺入BM。卵泡末端高水平的ADAMTS-A通常是不必要的,但当转录升高时会抑制Col4掺入。同时,末端表达的金属蛋白酶Stall增加了后部Col4的周转。我们的数据展示了一个器官如何利用具有细胞内和细胞外活性的ECM蛋白酶的模式表达来确定控制形状的BM特性。