Moreno Mauricio, Muñoz Rosana, Aroca Francisco, Labarca Mariana, Brandan Enrique, Larraín Juan
Department of Cell and Molecular Biology, Centre for Cell Regulation and Pathology, Millennium Nucleus in Developmental Biology, Faculty of Biological Sciences, P. Universidad Católica de Chile, Alameda, Santiago, Chile.
EMBO J. 2005 Apr 6;24(7):1397-405. doi: 10.1038/sj.emboj.7600615. Epub 2005 Mar 17.
The BMP4 signaling pathway plays key roles during early embryonic development and for maintenance of adult homeostasis. In the extracellular space, BMP4 activity is regulated by a group of interacting molecules including the BMP antagonist Chordin, the metalloproteinase Tolloid and Twisted gastrulation (Tsg). In this study, we identified Biglycan (Bgn), a member of the small leucine-rich proteoglycan family, as a new extracellular modulator of BMP4 signaling. Xenopus Bgn (xBgn) is expressed uniformly in the ectoderm and mesoderm and their derivatives during development. Microinjection of Bgn mRNA induced secondary axes, dorsalized the mesoderm and inhibited BMP4 activity in Xenopus embryos. Biochemical experiments showed that Bgn binds BMP4 and Chordin, interaction that increased binding of BMP4 to Chordin. Bgn was also able to improve the efficiency of Chordin-Tsg complexes to block BMP4 activity. Using antisense morpholinos, we demonstrated that Bgn required Chordin to induce double axes in Xenopus. This work unveiled a new function for Bgn, its ability to regulate BMP4 signaling through modulation of Chordin anti-BMP4 activity.
骨形态发生蛋白4（BMP4）信号通路在胚胎早期发育以及维持成体稳态过程中发挥着关键作用。在细胞外空间，BMP4的活性受一组相互作用分子的调控，这些分子包括BMP拮抗剂脊索蛋白（Chordin）、金属蛋白酶类 tolloid 以及扭结原肠胚形成蛋白（Tsg）。在本研究中，我们鉴定出富含亮氨酸小分子蛋白聚糖家族成员双糖链蛋白聚糖（Bgn）是BMP4信号通路一种新的细胞外调节剂。非洲爪蟾的Bgn（xBgn）在发育过程中在外胚层、中胚层及其衍生物中均匀表达。在非洲爪蟾胚胎中显微注射Bgn信使核糖核酸（mRNA）可诱导形成次生轴，使中胚层背化并抑制BMP4活性。生化实验表明，Bgn可结合BMP4和脊索蛋白，这种相互作用增强了BMP4与脊索蛋白的结合。Bgn还能够提高脊索蛋白-Tsg复合物阻断BMP4活性的效率。利用反义吗啉代寡核苷酸，我们证明在非洲爪蟾中Bgn需要脊索蛋白来诱导形成双轴。这项工作揭示了Bgn的一项新功能，即其能够通过调节脊索蛋白的抗BMP4活性来调控BMP4信号通路。
