RNA-Binding Protein Rbm24 as a Multifaceted Post-Transcriptional Regulator of Embryonic Lineage Differentiation and Cellular Homeostasis

RNA-binding proteins control the metabolism of RNAs at all stages of their lifetime. They are critically required for the post-transcriptional regulation of gene expression in a wide variety of physiological and pathological processes. Rbm24 is a highly conserved RNA-binding protein that displays strongly regionalized expression patterns and exhibits dynamic changes in subcellular localization during early development. There is increasing evidence that it acts as a multifunctional regulator to switch cell fate determination and to maintain tissue homeostasis. Dysfunction of Rbm24 disrupts cell differentiation in nearly every tissue where it is expressed, such as skeletal and cardiac muscles, and different head sensory organs, but the molecular events that are affected may vary in a tissue-specific, or even a stage-specific manner. Recent works using different animal models have uncovered multiple post-transcriptional regulatory mechanisms by which Rbm24 functions in key developmental processes. In particular, it represents a major splicing factor in muscle cell development, and plays an essential role in cytoplasmic polyadenylation during lens fiber cell terminal differentiation. Here we review the advances in understanding the implication of Rbm24 during development and disease, by focusing on its regulatory roles in physiological and pathological conditions

Rôles des homéoprotéines Six et de leurs co-facteurs Eya dans différentes étapes de la myogenèse de la souris

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

International audienceEmbryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk and limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within the somites undergo proliferation, migration and differentiation to elongate and fuse into multinucleated functional myofibers. Skeletal muscle is the most abundant tissue of the body and has the remarkable ability to self-repair by re-activating the myogenic program in muscle stem cells, known as satellite cells. Post-transcriptional regulation of gene expression mediated by RNA-binding proteins is critically required for muscle development during embryogenesis and for muscle homeostasis in the adult. Differential subcellular localization and activity of RNA-binding proteins orchestrates target gene expression at multiple levels to regulate different steps of myogenesis. Dysfunctions of these post-transcriptional regulators impair muscle development and homeostasis, but also cause defects in motor neurons or the neuromuscular junction, resulting in muscle degeneration and neuromuscular disease. Many RNA-binding proteins, such as members of the muscle blind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) families, display both overlapping and distinct targets in muscle cells. Thus they function either cooperatively or antagonistically to coordinate myoblast proliferation and differentiation. Evidence is accumulating that the dynamic interplay of their regulatory activity may control the progression of myogenic program as well as stem cell quiescence and activation. Moreover, the role of RNA-binding proteins that regulate post-transcriptional modification in the myogenic program is far less understood as compared with transcription factors involved in myogenic specification and differentiation. Here we review past achievements and recent advances in understanding the functions of RNA-binding proteins during skeletal muscle development, regeneration and disease, with the aim to identify the fundamental questions that are still open for further investigations

Editorial: Post-transcriptional regulation of embryonic and adult myogenesis

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RNA-binding protein Rbm24 as a multifaceted post-transcriptional regulator of embryonic lineage differentiation and cellular homeostasis

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Expression patterns of Rbm24 in lens, nasal epithelium, and inner ear during mouse embryonic development

International audienceBackground: RNA-binding proteins plays critical roles in several post-transcriptional regulatory processes. The RNA-binding protein, Rbm24, has been shown to be involved in the development of the heart and skeletal muscles by regulating different post-transcriptional processes such as splicing and stabilization of specific target mRNAs. Here, by performing a detailed expression and localization analysis in mice embryos, we show that Rbm24 protein is not only expressed in heart and skeletal muscles as previously reported, but it is also strongly and specifically detected in specific regions of all the head sensory organs during mouse development. Results: Rbm24 expression is indeed found to be activated in the lens, in the sensory olfactory epithelium and in mechanosensory cells of the auditory and vestibular systems. Within these territories, Rbm24 is shown to be restricted to distinct subdomains, potentially regulating cell specificity and proliferation. Moreover, Rbm24 protein is found to be restricted to the cytoplasmic compartment in all these organs, thus providing clues to the posttranscrip-tional activity that it may exert in these cells. Conclusions: Altogether, these results highlight that Rbm24 may potentially function as a novel key regulator for the development of the eye, nasal epithelium, and inner ear in vertebrates

Emerging Roles of RNA-Binding Proteins in Inner Ear Hair Cell Development and Regeneration

International audienceRNA-binding proteins (RBPs) regulate gene expression at the post-transcriptional level. They play major roles in the tissue- and stage-specific expression of protein isoforms as well as in the maintenance of protein homeostasis. The inner ear is a bi-functional organ, with the cochlea and the vestibular system required for hearing and for maintaining balance, respectively. It is relatively well documented that transcription factors and signaling pathways are critically involved in the formation of inner ear structures and in the development of hair cells. Accumulating evidence highlights emerging functions of RBPs in the post-transcriptional regulation of inner ear development and hair cell function. Importantly, mutations of splicing factors of the RBP family and defective alternative splicing, which result in inappropriate expression of protein isoforms, lead to deafness in both animal models and humans. Because RBPs are critical regulators of cell proliferation and differentiation, they present the potential to promote hair cell regeneration following noise- or ototoxin-induced damage through mitotic and non-mitotic mechanisms. Therefore, deciphering RBP-regulated events during inner ear development and hair cell regeneration can help define therapeutic strategies for treatment of hearing loss. In this review, we outline our evolving understanding of the implications of RBPs in hair cell formation and hearing disease with the aim of promoting future research in this field

Relationship between neural crest cells and cranial mesoderm during head muscle development

Background: In vertebrates, the skeletal elements of the jaw, together with the connective tissues and tendons, originate from neural crest cells, while the associated muscles derive mainly from cranial mesoderm. Previous studies have shown that neural crest cells migrate in close association with cranial mesoderm and then circumscribe but do not penetrate the core of muscle precursor cells of the branchial arches at early stages of development, thus defining a sharp boundary between neural crest cells and mesodermal muscle progenitor cells. Tendons constitute one of the neural crest derivatives likely to interact with muscle formation. However, head tendon formation has not been studied, nor have tendon and muscle interactions in the head. Methodology/Principal Findings: Reinvestigation of the relationship between cranial neural crest cells and muscle precursor cells during development of the first branchial arch, using quail/chick chimeras and molecular markers revealed several novel features concerning the interface between neural crest cells and mesoderm. We observed that neural crest cells migrate into the cephalic mesoderm containing myogenic precursor cells, leading to the presence of neural crest cells inside the mesodermal core of the first branchial arch. We have also established that all the forming tendons associated with branchiomeric and eye muscles are of neural crest origin and express the Scleraxis marker in chick and mouse embryos. Moreover, analysis of Scleraxis expression in the absence of branchiomeric muscles in Tbx1 2/2 mutant mice, showed tha

Rbm24 displays dynamic functions required for myogenic differentiation during muscle regeneration

International audienceAbstract Skeletal muscle has a remarkable capacity of regeneration after injury, but the regulatory network underlying this repair process remains elusive. RNA-binding proteins play key roles in the post-transcriptional regulation of gene expression and the maintenance of tissue homeostasis and plasticity. Rbm24 regulates myogenic differentiation during early development, but its implication in adult muscle is poorly understood. Here we show that it exerts multiple functions in muscle regeneration. Consistent with its dynamic subcellular localization during embryonic muscle development, Rbm24 also displays cytoplasm to nucleus translocation during C2C12 myoblast differentiation. In adult mice, Rbm24 mRNA is enriched in slow-twitch muscles along with myogenin mRNA. The protein displays nuclear localization in both slow and fast myofibers. Upon injury, Rbm24 is rapidly upregulated in regenerating myofibers and accumulates in the myonucleus of nascent myofibers. Through satellite cell transplantation, we demonstrate that Rbm24 functions sequentially to regulate myogenic differentiation and muscle regeneration. It is required for myogenin expression at early stages of muscle injury and for muscle-specific pre-mRNA alternative splicing at late stages of regeneration. These results identify Rbm24 as a multifaceted regulator of myoblast differentiation. They provide insights into the molecular pathway orchestrating the expression of myogenic factors and muscle functional proteins during regeneration.Skeletal muscle has a remarkable capacity of regeneration after injury, but the regulatory network underlying this repair process remains elusive. RNA-binding proteins play key roles in the post-transcriptional regulation of gene expression and the maintenance of tissue homeostasis and plasticity. Rbm24 regulates myogenic differentiation during early development, but its implication in adult muscle is poorly understood. Here we show that it exerts multiple functions in muscle regeneration. Consistent with its dynamic subcellular localization during embryonic muscle development, Rbm24 also displays cytoplasm to nucleus translocation during C2C12 myoblast differentiation. In adult mice, Rbm24 mRNA is enriched in slow-twitch muscles along with myogenin mRNA. The protein displays nuclear localization in both slow and fast myofibers. Upon injury, Rbm24 is rapidly upregulated in regenerating myofibers and accumulates in the myonucleus of nascent myofibers. Through satellite cell transplantation, we demonstrate that Rbm24 functions sequentially to regulate myogenic differentiation and muscle regeneration. It is required for myogenin expression at early stages of muscle injury and for muscle-specific pre-mRNA alternative splicing at late stages of regeneration. These results identify Rbm24 as a multifaceted regulator of myoblast differentiation. They provide insights into the molecular pathway orchestrating the expression of myogenic factors and muscle functional proteins during regeneration

Comparison of <i>MyoR</i> and <i>MyoD</i> expression domains during chick first branchial arch development.

<p>(A) Lateral view of a HH20 chick embryo hybridized with a <i>MyoR</i> probe. HH20 (B,C), HH22 (D,E) HH24 (F,G) and HH26 (H,I) embryos were frontally sectioned at the head level. The plane of section is indicated in the panel A. Adjacent sections from each stage were hybridized with DIG-labelled antisense probes for either <i>MyoR</i> (B,D,F,H) or <i>MyoD</i> (C,E,G,I). <i>MyoR</i> delineates the myogenic core of the first branchial arch (B,D,F) and is subsequently expressed in all branchiomeric muscles (H). <i>MyoD</i> transcripts are first detected in a lateral sub-region of the <i>MyoR</i> domain at HH20 (B,C, arrows) and HH22 (D,E, arrows), then spread progressively from lateral to medial regions to overlap with the <i>MyoR</i> domain in branchiomeric muscles (E,G,I). (D–G) Arrows point to the lateral domains of the core, while arrowheads show the medial domain of the core. (H,I) Arrows indicate the branchiomeric muscles expressing both <i>MyoR</i> (H) and <i>MyoD</i> (I). (A) Arrowheads indicate the hypaxial lips at the interlimb level, expressing <i>MyoR</i>. BA1, first branchial arch, di, diencephalon; e, eye; fl, forelimb; hl, hindlimb; mb, mandibular arch; mes, mesenchephalon; MR, medial rectus; mx, maxillary arch; ph, pharynx; tel, telencephalon; VO, ventral oblique; VR, ventral rectus.</p