| 作者： |
Ye, Ding; Wang, Xiaosi; Wei, Changyong; He, Mudan; Wang, Houpeng; Wang, Yanwu; Zhu, Zuoyan; Sun, Yonghua |
| 论文摘要： |
During vertebrate early embryogenesis, the ventral development is directed by the ventral-to-dorsal activity gradient of the bone morphogenetic protein (BMP) signaling. As secreted ligands, the extracellular traffic of BMP has been extensively studied. However, it remains poorly understood that how BMP ligands are secreted from BMP-producing cells. In this work, we show the dominant role of Marcksb controlling the secretory process of Bmp2b via interaction with Hsp70 in vivo. We firstly carefully characterized the role of Marcksb in promoting BMP signaling during dorsoventral axis formation through knockdown approach. We then showed that Marcksb cell autonomously regulates the trafficking of Bmp2b from producing cell to the extracellular space and both the total and the extracellular Bmp2b was decreased in Marcksb-deficient embryos. However, neither the zygotic mutant of marcksb (Zmarcksb) nor the maternal zygotic mutant of marcksb (MZmarcksb) showed any defects of dorsalization. In contrast, the MZmarcksb embryos even showed increased BMP signaling activity as measured by expression of BMP targets, phosphorylated Smad1/5/9 levels and imaging of Bmp2b, suggesting that a phenomenon of genetic over-compensation arose. Finally, we revealed that the over-compensation effects of BMP signaling in MZmarcksb was achieved through a sequential up-regulation of MARCKS-family members Marcksa, Marcksl1a and Marcksl1b, and MARCKS-interacting protein Hsp70.3. We concluded that the Marcksb modulates BMP signaling through regulating the secretory pathway of Bmp2b. Author summary Bone morphogenetic proteins (BMPs) are extracellular proteins which belong to the transforming growth factor-beta (TGF-beta) superfamily. BMP signaling is essential for embryonic development, organogenesis, and tissue regeneration and homeostasis, and tightly linked to various diseases and tumorigenesis. However, as secreted proteins, how BMPs are transported and secreted from BMP-producing cells remains poorly understood. In this study, we showed that Marcksb interacts with a molecular chaperon-Hsp70.3 to mediate the secretory pathway of BMP ligands during early development of zebrafish. Moreover, we discovered a novel phenomenon of genetic over-compensation in the genetic knock-out mutants of marcksb. To our knowledge, this is the first report that reveals the molecules and their related trafficking system mediating the secretion of BMPs. Considering the wide distribution of BMP and MARCKS within the human body, our work may shed light on the studies of BMPs secretion in organogenesis and adult tissue homeostasis. The finding of MARCKS in controlling BMP secretion may provide potential therapeutic targets for modulating the activity of BMP signaling and thus will be of interest to clinical research. |
