Induction and differentiation during vertebrate embryonic development

Our team is interested in understanding the molecular and cellular mechanisms that control muscle development in vertebrate embryos. We focus our research on the post-transcriptional regulation of embryonic myogenesis and adult muscle differentiation by RNA-binding proteins.We use zebrafish as a model, which is most suitable for in vivo and in vitro analyses using cell and molecular biology, genetics, and living imaging approaches. Our goal is to decipher common mechanisms underlying early development and human pathologies. The research interests include important aspects of post-transcriptional regulations of gene expression during early development.

The post-transcriptional regulation of gene expression orchestrated by RNA-binding proteins is involved in a wide variety of physiological and pathological processes. The evolutionarily conserved RBM24 (RNA-Binding Motif Protein 24) is highly expressed in muscles and head sensory organs of all vertebrate embryos. In addition, it displays dynamic subcellular localization during cellular differentiation. We have made the unprecedented finding that RBM24 plays a key role in cytoplasmic polyadenylation to control mRNA translation. Thus, our objective is to understand how RBM24 regulates protein homeostasis during muscle cell differentiation and regeneration.

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Cell differentiation is a fundamental process that generates all the cell types of our body from a fertilized egg. Its deregulation causes defective development and the occurrence of various pathological conditions. In this context, we have been engaged in understanding the molecular events during muscle cell development in vertebrate embryos. In particular, we focus our research on the role of RNA-binding proteins in the post-transcriptional regulation of muscle differentiation and regeneration.

RNA-binding proteins (RBPs) control RNA metabolism at multiple levels, and are critical for maintaining the homeostasis of protein synthesis during early development and in adult life.Due to their importance in the temporal and spatial control of gene expression, a growing number of human diseases are associated with RNAs and RBPs. Analyses of RBM24 loss of function reveal that it is critically required for cellular differentiation. Deficiency in its expression level could be the cause of congenital disorders, such as cardiomyopathy, myopathy or blindness, which affect the normal function of related tissues where crucial roles of this gene have been demonstrated in different animal models. Thus, our aim is to decipher the post-transcriptional mechanisms mediated by RBM24 in muscle development and regeneration. We will focus our research on the identification of its interacting partners and mRNA targets to understand how it regulates mRNA stability, polyadenylation and translation.

Highlights

  1. Dishevelled (Dvl) protein mediates the activation of both canonical and non-canonical Wnt signaling, but the mechanism remains unclear. Moreover, its requirement for the activation of maternal Wnt/ß-catenin signaling in dorsal axis specification has been largely enigmatic. We have demonstrated that the carboxyl-terminus of Dvl plays an important role in regulating Dvl conformational changes in canonical versus non-canonical Wnt signaling, and that Dvl maternal function is dispensable for dorsal axis formation, but indispensable for cellular polarization during morphogenetic movements (Elife 2016; Nat Commun 2017; J Biol Chem 2017; PloS Genet 2018; Front Cell Dev Biol 2020).
  2. Transcriptional derepression and post-translational regulation of gene expression play important roles in tumorigenesis, but their implication in early development remains elusive. We demonstrated that XDSCR6, a Xenopus homolog of human Down syndrome critical region protein 6, regulates mesoderm and embryonic axis formation through derepression of polycomb group (PcG) proteins, including Ezh2. Moreover, we found that XDSCR6 and Ezh2 play an opposite role in Stat3 protein methylation and represent important regulators ofStat3 transcriptional activity in mesoderm patterning during early development (Development 2013; Wiley Interdiscip Rev Dev Biol 2016; J Biol Chem 2020).
  3. The RNA-binding protein RBM24 displays highly conserved expression pattern in vertebrate embryos. We showed that it represents a direct target of MyoD and is required for myogenic differentiation. Furthermore, we found that RBM24 displays dynamic subcellular localization and post-transcriptional functions during muscle differentiation and regeneration. More recently and importantly, we have provided the unprecedented finding that it interacts with the cytoplasmic polyadenylation complex to regulate poly(A) tail lengths of crystallin mRNAs during lens terminal differentiation (Mech Dev 2010, 2014; Dev Dyn 2018; PNAS 2020; Cells 2020; Sci Rep 2021).

Future directions

Transcriptional regulation of muscle differentiation is well understood, but post-transcriptional control of this process remains largely elusive.To understand the post-transcriptional mechanism implicating RBM24 in myogenic differentiation, we will perform large-scale analysis of Rbm24-regulated events during myogenesis, including the expression, polyadenylation, stability and translation efficiency of muscle-specific mRNAs. We will also identify novel RBM24-interacting partners and determine the functional interaction between RBM24 and the cytoplasmic polyadenylation complex in the regulation of muscle cell differentiation and regeneration.

Collaborations

Genome-editing and generation of zebrafish mutant and transgenic lines by CRISPR/Cas9 approach to study post-transcriptional regulation of cell differentiation - School of Life Science, Shandong University, Qingdao, China.