The Gyc76C Receptor Guanylyl Cyclase and the Foraging cGMP-Dependent Kinase Regulate Extracellular Matrix Organization and BMP Signaling in the Developing Wing of Drosophila melanogaster

The developing crossveins of the wing of Drosophila melanogaster are specified by long-range BMP signaling and are especially sensitive to loss of extracellular modulators of BMP signaling such as the Chordin homolog Short gastrulation (Sog). However, the role of the extracellular matrix in BMP signaling and Sog activity in the crossveins has been poorly explored. Using a genetic mosaic screen for mutations that disrupt BMP signaling and posterior crossvein development, we identify Gyc76C, a member of the receptor guanylyl cyclase family that includes mammalian natriuretic peptide receptors. We show that Gyc76C and the soluble cGMP-dependent kinase Foraging, likely linked by cGMP, are necessary for normal refinement and maintenance of long-range BMP signaling in the posterior crossvein. This does not occur through cell-autonomous crosstalk between cGMP and BMP signal transduction, but likely through altered extracellular activity of Sog. We identify a novel pathway leading from Gyc76C to the organization of the wing extracellular matrix by matrix metalloproteinases, and show that both the extracellular matrix and BMP signaling effects are largely mediated by changes in the activity of matrix metalloproteinases. We discuss parallels and differences between this pathway and other examples of cGMP activity in both Drosophila melanogaster and mammalian cells and tissues.

黑腹果蝇（Drosophila melanogaster）翅膀发育中的交叉脉由长程骨形态发生蛋白（Bone Morphogenetic Protein, BMP）信号通路特化形成，且对BMP信号的细胞外调控因子的缺失尤为敏感，这类调控因子包含Chordin同源蛋白短原肠胚形成蛋白（Short gastrulation, Sog）。然而，细胞外基质在交叉翅脉的BMP信号通路及Sog活性中所发挥的作用却鲜有研究。我们通过针对破坏BMP信号通路与后交叉脉发育的突变体开展遗传嵌合筛选，鉴定出Gyc76C——一类包含哺乳动物利钠肽受体的受体鸟苷酸环化酶家族成员。研究证实，Gyc76C与可溶性环磷酸鸟苷（cyclic guanosine monophosphate, cGMP）依赖性激酶Foraging（二者大概率通过cGMP建立关联），对于后交叉脉处长程BMP信号通路的正常精细化调控与维持是必需的。该过程并非通过cGMP与BMP信号转导之间的细胞自主性串扰实现，而是极有可能通过改变Sog的细胞外活性来完成。我们发现了一条全新的信号通路：该通路由Gyc76C介导，通过基质金属蛋白酶（matrix metalloproteinases）调控翅膀细胞外基质的组装；同时证实，细胞外基质与BMP信号通路相关的效应主要由基质金属蛋白酶的活性变化所介导。我们还讨论了该通路与黑腹果蝇及哺乳动物细胞、组织中其他cGMP活性相关实例之间的共性与差异。