Marcksb Regulates BMP Secretion and Genetic Over-compensation Arises in Zebrafish MZmarcksb Mutants

Bone morphogenetic proteins (BMPs) mediated signaling is essential for embryonic development, organ formation, and tissue regeneration. It also tightly linked to various diseases and tumorigenesis. However, as secreted proteins, how BMPs are transported and secreted from BMP-producing cells remains poorly understood. 

Recently, SUN Yonghua’s group at Institute of Hydrobiology (IHB) of Chinese Academy of Sciences has published a research article on PLOS Genetics describing their recent finding on the novel role of the myristoylated alanine-rich C-kinase substrate (MARCKS) proteins in BMPs secretion. 

In this study, they found that the MARCKS family member -Marcksb mediates the cell fate of the embryonic ventral axis via controlling the activity of BMP signaling. The cell transplantation assay showed a cell-autonomous role of Marcksb on regulating the secretion of Bmp2b from producing cell to the extracellular space. The trafficking of Bmp2b is tightly related to the phosphorylation and de-phosphorylation status of Marcksb.  

Furtherly, they combined in vivo and in vitro experiments to reveal that Marcksb interacts with a molecular chaperon–Hsp70.3 to mediate the secretory pathway of BMP ligands. They discovered a novel phenomenon of "genetic over-compensation" in the genetic knockout mutants of marcksb.  

This over-compensation effect of BMP signaling was achieved through a sequential up-regulation of MARCKS-family members Marcksa, Marcksl1a and Marcksl1b, and MARCKS-interacting protein Hsp70.3. Thus, the Marcksb modulates BMP signaling through regulating the secretory pathway of Bmp2b. 

This study is the first report that reveals the molecules and their related trafficking system mediating the secretion of BMPs. Since the BMPs and MARCKS are widely distributed within the human body, this work may shed light on other studies related to BMPs secretion in a broader field. 

A model shows MARCKS-mediated BMPs secretory process in the cells of wildtype embryos, marcksb knockdown embryos (marcksb KD) and maternal-zygotic knockout embryos of marcksb (marcksb KO). In wildtype embryo, Marcksb dominantly interacts with Hsp70 to mediate the secretion of BMPs. In marcksb KD embryos, reduction of Marcksb proteins interferes the BMPs secreted out from cells. In marcksb KO embryos, other up-regulated MARCKS family members and Hsp70.3 are interact to produce lots of functional MARCKS-Hsp70 complex, which further promote the secretion of BMPs. (Image by IHB)