Mga Modulates Bmpr1a Activity by Antagonizing Bs69 in Zebrafish.

Xiaoyun Sun,Yuhua Sun,Yanyong Zhang,Ji Chen,Scott Dougan,Mumingjiang Munisha

doi:10.3389/fcell.2018.00126

Abstract

MAX giant associated protein (MGA) is a dual transcriptional factor containing both T-box and bHLHzip DNA binding domains. In vitro studies have shown that MGA functions as a transcriptional repressor or activator to regulate transcription of promotors containing either E-box or T-box binding sites. BS69 (ZMYND11), a multidomain-containing (i.e., PHD, BROMO, PWWP, and MYND) protein, has been shown to selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3), modulates RNA Polymerase II elongation, and functions as RNA splicing regulator. Mutations in MGA or BS69 have been linked to multiple cancers or neural developmental disorders. Here, by TALEN and CRISPR/Cas9-mediated loss of gene function assays, we show that zebrafish Mga and Bs69 are required to maintain proper Bmp signaling during early embryogenesis. We found that Mga protein localized in the cytoplasm modulates Bmpr1a activity by physical association with Zmynd11/Bs69. The Mynd domain of Bs69 specifically binds the kinase domain of Bmpr1a and interferes with its phosphorylation and activation of Smad1/5/8. Mga acts to antagonize Bs69 and facilitate the Bmp signaling pathway by disrupting the Bs69–Bmpr1a association. Functionally, Bmp signaling under control of Mga and Bs69 is required for properly specifying the ventral tailfin cell fate.

Highlights

Bone morphogenetic proteins (BMPs) comprise a subgroup of the TGF-beta family of secreted signaling molecules
Out of 12 potential founders, we identified two fish in which mga gene was mutated at the TALEN cleavage site in the exon 2
We concluded that Bs69 negatively regulates Bmp signaling by physical association with Bmp receptor 1a (Bmpr1a), which interferes with its phosphorylation and activation of Smad1/5

Summary

Introduction

Bone morphogenetic proteins (BMPs) comprise a subgroup of the TGF-beta family of secreted signaling molecules. They transduce their signal by extracellular binding to membrane protein complex consisting of a type I receptor (BMPRI) and a type II receptor (BMPRII). Given its importance in development and homeostasis, Bmp signaling is tightly regulated at the extra- and intracellular levels, by numerous factors such as Noggin, Chordin, Smad, and Fkbp1A (Wang et al, 2014).MAX’s giant associated protein (MGA) was first identified as a MAX interacting protein by a yeast two hybrid assay in a mouse embryonic day e9.5 and e10.5 cDNA library (Hurlin et al, 1999). In addition to the bHLHZip domain, MGA contains a second

Methods

Results

Conclusion