Developmental origin of tendon diversity in .

Myogenesis is a developmental process that is largely conserved in both and higher organisms. Consequently, the fruit fly is an excellent model for identifying the genes and mechanisms involved in muscle development. Moreover, there is growing evidence indicating that specific conserved genes and signaling pathways govern the formation of tissues that connect the muscles to the skeleton.

Deregulations of miR-1 and its target Multiplexin promote dilated cardiomyopathy associated with myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. It is caused by the excessive expansion of noncoding CTG repeats, which when transcribed affects the functions of RNA-binding factors with adverse effects on alternative splicing, processing, and stability of a large set of muscular and cardiac transcripts. Among these effects, inefficient processing and down-regulation of muscle- and heart-specific miRNA, miR-1, have been reported in DM1 patients, but the impact of reduced miR-1 on DM1 pathogenesis has been unknown.

Dual-Color Live Imaging of Adult Muscle Stem Cells in the Embryonic Tissues .

Adult muscle stem cells (MuSCs) show remarkable capability in repairing injured tissues. Studying MuSCs in suitable model organisms, which show strong homology with vertebrate counterparts, helps in dissecting the mechanisms regulating their behavior. Additionally, ease of handling and access to technological tools make model organisms well suited for studying biological processes that are conserved across species.

Transcriptomic and Genetic Analyses Identify the Krüppel-Like Factor Dar1 as a New Regulator of Tube-Shaped Long Tendon Development.

To ensure locomotion and body stability, the active role of muscle contractions relies on a stereotyped muscle pattern set in place during development. This muscle patterning requires a precise assembly of the muscle fibers with the skeleton via a specialized connective tissue, the tendon. Like in vertebrate limbs, leg muscles make connections with specific long tendons that extend through different segments.

Diversification of muscle types in Drosophila embryos.

Drosophila embryonic somatic muscles represent a simple and tractable model system to study the gene regulatory networks that control diversification of cell types. Somatic myogenesis in Drosophila is initiated by intrinsic action of the mesodermal master gene twist, which activates a cascade of transcriptional outputs including myogenic differentiation factor Mef2, which triggers all aspects of the myogenic differentiation program. In parallel, the expression of a combinatorial code of identity transcription factors (iTFs) defines discrete particular features of each muscle fiber, such as number of fusion events, and specific attachment to tendon cells or innervation, thus ensuring diversification of muscle types.

Heart as a Model for Cardiac Development and Diseases.

The heart, also referred to as the dorsal vessel, pumps the insect blood, the hemolymph. The bilateral heart primordia develop from the most dorsally located mesodermal cells, migrate coordinately, and fuse to form the cardiac tube. Though much simpler, the fruit fly heart displays several developmental and functional similarities to the vertebrate heart and, as we discuss here, represents an attractive model system for dissecting mechanisms of cardiac aging and heart failure and identifying genes causing congenital heart diseases.

A polarized nucleus-cytoskeleton-ECM connection in migrating cardioblasts controls heart tube formation in Drosophila.

The formation of the cardiac tube is a remarkable example of complex morphogenetic processes conserved from invertebrates to humans. It involves coordinated collective migration of contralateral rows of cardiac cells. The molecular processes underlying the specification of cardioblasts (CBs) prior to migration are well established and significant advances have been made in understanding the process of lumen formation.

Gelsolin and dCryAB act downstream of muscle identity genes and contribute to preventing muscle splitting and branching in Drosophila.

A combinatorial code of identity transcription factors (iTFs) specifies the diversity of muscle types in Drosophila. We previously showed that two iTFs, Lms and Ap, play critical role in the identity of a subset of larval body wall muscles, the lateral transverse (LT) muscles. Intriguingly, a small portion of ap and lms mutants displays an increased number of LT muscles, a phenotype that recalls pathological split muscle fibers in human.

Zebrafish as a Model for the Study of Lipid-Lowering Drug-Induced Myopathies.

Drug-induced myopathies are classified as acquired myopathies caused by exogenous factors. These pathological conditions develop in patients without muscle disease and are triggered by a variety of medicaments, including lipid-lowering drugs (LLDs) such as statins, fibrates, and ezetimibe. Here we summarise the current knowledge gained via studies conducted using various models, such as cell lines and mammalian models, and compare them with the results obtained in zebrafish () studies.

The relationship between muscle stem cells and motor neurons.

Neuromuscular system is constituted of multi-fibrillar muscles, tendons, motor neurons and associated muscle stem cells. Stereotyped pattern of muscle innervation and muscle-specific interactions with tendon cells suggest that neuromuscular system develops in a coordinated way. Remarkably, upon regeneration, coordinated assembly of all neuromuscular components is also critical to rebuild functional muscle.

Genetic Control of Muscle Diversification and Homeostasis: Insights from .

In the fruit fly, , the larval somatic muscles or the adult thoracic flight and leg muscles are the major voluntary locomotory organs. They share several developmental and structural similarities with vertebrate skeletal muscles. To ensure appropriate activity levels for their functions such as hatching in the embryo, crawling in the larva, and jumping and flying in adult flies all muscle components need to be maintained in a functionally stable or homeostatic state despite constant strain.

Insulin-dependent Non-canonical Activation of Notch in Drosophila: A Story of Notch-Induced Muscle Stem Cell Proliferation.

Notch plays multiple roles both in development and in adult tissue homeostasis. Notch was first identified in Drosophila in which it has then been extensively studied. Among the flag-ship Notch functions we could mention its capacity to keep precursor and stem cells in a nondifferentiated state but also its ability to activate cell proliferation that in some contexts could led to cancer.

adult muscle precursor cells contribute to motor axon pathfinding and proper innervation of embryonic muscles.

Despites several decades of studies on the neuromuscular system, the relationship between muscle stem cells and motor neurons remains elusive. Using the model, we provide evidence that adult muscle precursors (AMPs), the muscle stem cells, interact with the motor axons during embryogenesis. AMPs not only hold the capacity to attract the navigating intersegmental (ISN) and segmental a (SNa) nerve branches, but are also mandatory to the innervation of muscles in the lateral field.

deregulation is associated with cardiac conduction defects in myotonic dystrophy type 1.

Cardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a CTG repeat disorder involving misbalance between two RNA binding factors, MBNL1 and CELF1. However, how DM1 condition translates into conduction disorders remains poorly understood. Here we simulated MBNL1 and CELF1 misbalance in the heart and performed TU-tagging-based RNAseq of cardiac cells.

Odd-skipped and Stripe act downstream of Notch to promote the morphogenesis of long appendicular tendons in .

Multiple tissue interactions take place during the development of the limb musculoskeletal system. While appendicular myogenesis has been extensively studied, development of connective tissue associated with muscles has received less attention. In the developing leg, tendon-like connective tissue arises from clusters of epithelial cells that invaginate into the leg cavity and then elongate to form internal tube-shape structures along which muscle precursors are distributed.

Dissecting Pathogenetic Mechanisms and Therapeutic Strategies in Models of Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1), the most common cause of adult-onset muscular dystrophy, is autosomal dominant, multisystemic disease with characteristic symptoms including myotonia, heart defects, cataracts and testicular atrophy. DM1 disease is being successfully modelled in allowing to identify and validate new pathogenic mechanisms and potential therapeutic strategies. Here we provide an overview of insights gained from fruit fly DM1 models, either: (i) fundamental with particular focus on newly identified gene deregulations and their link with DM1 symptoms; or (ii) applied via genetic modifiers and drug screens to identify promising therapeutic targets.

Developmental Expression and Functions of the Small Heat Shock Proteins in .

Heat shock proteins (Hsps) form a large family of evolutionarily conserved molecular chaperones that help balance protein folding and protect cells from various stress conditions. However, there is growing evidence that Hsps may also play an active role in developmental processes. Here, we take the example of developmental expression and function of one class of Hsps characterized by low molecular weight, the small Hsps (sHsps).

Drosophila Hsp67Bc hot-spot variants alter muscle structure and function.

The Drosophila Hsp67Bc gene encodes a protein belonging to the small heat-shock protein (sHSP) family, identified as the nearest functional ortholog of human HSPB8. The most prominent activity of sHSPs is preventing the irreversible aggregation of various non-native polypeptides. Moreover, they are involved in processes such as development, aging, maintenance of the cytoskeletal architecture and autophagy.

Bruno-3 regulates sarcomere component expression and contributes to muscle phenotypes of myotonic dystrophy type 1.

Steinert disease, or myotonic dystrophy type 1 (DM1), is a multisystemic disorder caused by toxic noncoding CUG repeat transcripts, leading to altered levels of two RNA binding factors, MBNL1 and CELF1. The contribution of CELF1 to DM1 phenotypes is controversial. Here, we show that the CELF1 family member, Bru3, contributes to pathogenic muscle defects observed in a model of DM1.

Distinct subsets of Eve-positive pericardial cells stabilise cardiac outflow and contribute to Hox gene-triggered heart morphogenesis in .

The heart, composed of discrete subsets of cardioblasts and pericardial cells, undergoes Hox-triggered anterior-posterior morphogenesis, leading to a functional subdivision into heart proper and aorta, with its most anterior part forming a funnel-shaped cardiac outflow. Cardioblasts differentiate into Tin-positive 'working myocytes' and Svp-expressing ostial cells. However, developmental fates and functions of heart-associated pericardial cells remain elusive.

Characterization of Drosophila Muscle Stem Cell-Like Adult Muscle Precursors.

Uncovering how muscle stem cells behave in quiescent and activated states is central to understand the basic rules governing normal muscle development and regeneration in pathological conditions. Specification of mesodermal lineages including muscle stemlike adult muscle precursors (AMPs) has been extensively studied in Drosophila providing an attractive framework for investigating muscle stem cell properties. Restricted number of AMP cells, relative ease in following their behavior, and large number of genetic tools available make fruit fly an attractive model system for studying muscle stem cells.

Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function.

The rapid progress in medicine, agriculture, and allied sciences has enabled the development of a large amount of potentially useful bioactive compounds, such as drugs and pesticides. However, there is another side of this phenomenon, which includes side effects and environmental pollution. To avoid or minimize the uncontrollable consequences of using the newly developed compounds, researchers seek a quick and effective means of their evaluation.

Beyond mice: Emerging and transdisciplinary models for the study of early-onset myopathies.

The use of the adapted models to decipher patho-physiological mechanisms of human diseases is always a great challenge. This is of particular importance for early-onset myopathies, in which pathological mutations often impact not only on muscle structure and function but also on developmental processes. Mice are currently the main animal model used to study neuromuscular disorders including the early-onset myopathies.

in the Heart of Understanding Cardiac Diseases: Modeling Channelopathies and Cardiomyopathies in the Fruitfly.

Cardiovascular diseases and, among them, channelopathies and cardiomyopathies are a major cause of death worldwide. The molecular and genetic defects underlying these cardiac disorders are complex, leading to a large range of structural and functional heart phenotypes. Identification of molecular and functional mechanisms disrupted by mutations causing channelopathies and cardiomyopathies is essential to understanding the link between an altered gene and clinical phenotype.