The Muscle Signalling Group, led by Professor Mathias Gautel, studies the genetic regulation of the development of the musculo-skeletal, cardiac and vascular systems, the proteins responsible for signalling and the structural integrity of muscle, and mutations that underlie the pathology of these tissues.
Molecular, cellular and biochemical and biophysical techniques are used to investigate the mechanisms that organise the smallest contractile unit of striated muscle, the sarcomere, and how sarcomeres cross-talk to mechanisms controlling muscle growth. Sarcomeres are complex macromolecular assemblies, built of many self-interacting proteins which are organised in a highly specific way into filamentous and anchoring structures.
One of our aims is to understand the basic programme of muscle formation, both for its intrinsic interest and because we believe that this will underlie muscle repair and amelioration of disease. We also aim to understand the molecular and cellular mechanisms of how muscle is repaired and how this goes awry in ageing or disease conditions. We believe that understanding the processes of muscle development and growth in simple vertebrates will have implications for muscle repair and maintenance in patients.
These approaches employ molecular and cell-based techniques (including: satellite cell culture, cardiomyocyte culture, zebrafish, chick and mouse embryology, in situ hybridisation analysis of gene expression, immunocytochemistry, microarrays, retroviral-mediated gene expression, protein expression, yeast two-hybrid) coupled with both reverse and forward based genetic strategies in different model systems (using transient and stable transgenics).
Associated research programmes
Associated staff research interests
Gene Regulatory Networks in musculoskeleletal development
A central question in developmental biology is how the onset of gene expression results in the differentiation of a multi-potential progenitor cell pool into subsets of divergent cell fates. Progenitor cells in somites differentiate in response to extracellular signals to produce skeletal muscles, muscle stem cells, cartilage, tendon, endothelial and smooth muscle cells. We are investigating how signals are integrated at the level of gene expression through Gene Regulatory Networks to produce these differential outputs.
Somite development and differentiation
The skeletal muscles of the trunk and limbs and the axial skelelton (ribs and vertebrae) originate in somites, which are formed, as pairs on each side of the neural tube, as distinctive blocks of mesodermal cells. The somites give rise to the trunk and limb muscles and the asscouated muscle stem cells, the cartilage of the vertebrae and ribs, the tendons associated with the vertebral column, blood vessels of the limb and the dermis.
The limb bud is an important embryological model for studying how the patterns of cells and tissues are established. Most studies, however, have focussed on the skeletal elements of the limb and there is a paucity of knowledge of the basis of muscle and muscle connective tissue (including tendons) patterning. We use transgenic models to investigate the formation of fully defined limb muscles and associated connective tissue and tendons to study reciprocal molecular and cellular interactions between these distinct cell types. Our transgenic models are used to research into muscle stem cell development, and tendon fibroblasts and tendon stem cells recruitment and maintenance. We use a variety of molecular and cellular techniques, including: gene expression analysis, transgenesis, gene knockouts, microarrays, ChIP, gel shift assays, bioinformatics, explant cultures, and in vitro cell culture.
- Kirilenko P, He G, Mankoo B, Mallo M, Jones R, Bobola N. (2011) Transient activation of Meox1 is an early component of the gene regulatory network downstream of Hoxa2. Mol Cell Biol. doi:10.1128/MCB.00705-10
- Perera S, Holt MR, Mankoo BS, Gautel M. (2011) Developmental regulation of MURF ubiquitin ligases and autophagy proteins nbr1, p62/SQSTM1 and LC3 during cardiac myofibril assembly and turnover. Dev Biol. 2011 351:46-61
- Otto A, Macharia R, Matsakas A, Valasek P, Mankoo BS, Patel K (2010) A hypoplastic model of skeletal muscle development displaying reduced foetal myoblast cell numbers, increased oxidative myofibres and improved specific tension capacity. Dev Biol. 343:51-62
- Reijntjes S, Francis-West P, Mankoo BS (2010) Retinoic acid is both necessary for and inhibits myogenic commitment and differentiation in the chick limb. Int. J. Dev. Biol. 54:125-34
- Skuntz S, Mankoo B, Nguyen M-T, Hustert E, Nakayama A, Tournier-Lasserve E, Wright CV, Pachnis V, Bharti K, Arnheiter H (2009) Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton. Dev. Biol. 332:383-95.
- Plachez C, Andrews W, Liapi A, Knoell B, Drescher U, Mankoo B, Zhe L, Mambetisaeva E, Annan A, Bannister L, Parnavelas J, Richards L, and Sundaresan V (2008) Robos are required for the correct targeting of retinalganglioncell axons in the visual pathway of the brain. Mol Cell Neurosci. 37:719-30.
- Reijntjes S, Stricker S, Mankoo BS (2007) A comparative analysis of Meox1 and Meox2 in the developing somites and limbs of the chick embryo. International Journal of Developmental Biology. 51:753-9
- Jukkola T, Trokovic R, Maj P, Lamberg A, Mankoo B, Pachnis V, Savilahti H and Partanen J (2005) Meox1Cre - a mouse line expressing Cre recombinase in somitic mesoderm. Genesis 43:148-53
- Rodrigo I, Bovolenta P, Mankoo BS, Imai K (2004) Meox homeodomain proteins are required for Bapx1 expression in the sclerotome and activate its transcription by direct binding to its promoter. Mol Cell Biol. 24:2757-66.
- Mankoo BS, Skuntz S, Harrigan I, Grigorieva E, Candia A, Wright CV, Arnheiter H, Pachnis V (2003)The concerted action of Meox homeobox genes is required upstream of genetic pathways essential for the formation, patterning and differentiation of somites.. Development. 130:4655-64.
020 7848 6594
We want to look at the organisation of the heart cell (cardiomyocyte) at a subcellular level; being interested mainly in cytoskeletal and signalling aspects:
- How are myofibrils and intercalated disks assembled in heart cells during development?
- How and if are myofibrils and intercalated disks affected in the diseased heart?
- What is the functional basis for the adaptations of cardiomyocytes during development and disease?
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We are interested in the networks of gene regulation that control early vertebrate development. The correct regulation of gene expression is crucial for cell lineages to become established during embryogenesis and for on-going differentiation of stem cells in the adult. Conversely, deregulation of gene expression may lead to cancerous changes and other disease states. Understanding the transcriptional programs that control gene expression and underlie cell differentiation is thus central to many aspects of biology.
During embryogenesis one of the earliest cell types to be specified is the mesoderm. Cells specified as mesoderm will go on to form tissues such as blood, skeletal muscle, cardiac muscle, kidney, cartilage and bone. As mesoderm forms key transcriptional regulators are activated which in turn activate a downstream network of target genes, ultimately leading to the formation of different tissue types.
Our long-term goal is to assemble and ultimately understand the networks of transcriptional regulation that underlie mesoderm specification and patterning during vertebrate embryogenesis. To achieve this we use zebrafish as a model system with a combination of experimental embryology, molecular biology, genomics and computational biology.
Recently, using chromatin immunoprecipitation combined with either genomic microarrays and next generation sequencing (techniques known as ChIP-chip and ChIP-seq respectively), we have identified genomic regions that are bound by three transcriptional regulators central to mesoderm formation in zebrafish - No tail, Tbx16 and Eomesodermin. In order to better understand how these factors regulate mesoderm formation we are are characterizing the target genes discovered by this approach using expression, promoter, functional and bioinformatic analyses.
Our on-going work continues to identify transcriptional targets of other key mesodermal regulators and to characterize downstream targets to place them in the network that regulates mesoderm formation in vertebrates.
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Investigation of the structure, dynamics and interactions of signalling, scaffolding and muscle proteins using NMR spectroscopy and other biophysical methods
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We are interested in the assembly and turnover of the contractile structures in cardiomyocytes, the sarcomeres, especially:
• how giant ruler proteins called titin and obscurin control the assembly of many other structural, contractile and signalling proteins into ordered sarcomeres,
• how mechanical forces regulate sarcomere assembly, as well as controlled turnover by the autophagy and ubiquitin-proteasomal pathways,
• how mutations in sarcomeric proteins, especially in titin and obscurin, affect sarcomere and turnover functions.
We use biochemical, biophysical, advanced cell imaging and structural methods to elucidate these basic functions and to translate them to human disease.
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The core research aim of the Zammit group is to understand the regulation of stem cell function in both normal and diseased skeletal muscle. The functional unit of skeletal muscle is the myofibre: a giant syncytial cell maintained by hundreds of myonuclei. Growth, maintenance or repair of the post-mitotic myofibre is performed by satellite cells. These resident stem cells are located on the surface of the muscle fibre, below the surrounding basal lamina.
Skeletal muscle is an archetypal adult stem cell model: maintenance and repair of functionally specialised post-mitotic cells is achieved by recruitment of undifferentiated precursors. Therefore, skeletal muscle provides an accessible model system with which to investigate adult stem cell control and function.
Research into satellite cell function is also relevant to understanding muscle diseases. Muscular dystrophies are all characterised by progressive skeletal muscle weakness and wasting, and have been mapped to at least 31 genetic loci. While muscular dystrophies vary in: age of onset; muscles affected and severity, the common factor is that the primary genetic defect ultimately results in muscle wasting, meaning that the homeostatic/regenerative process carried out by satellite cells is gradually compromised. By investigating the regulation of satellite cell function we can increase our understanding of why satellite cells initially maintain muscle function but then gradually fail in dystrophic conditions.
Theoretically, manipulation of the satellite cell pool in dystrophic muscle could both augment and prolong muscle function. This also has the advantage that it maintains a muscle environment still capable of responding to other forms of therapeutic intervention.
Current projects fall into 3 broad categories.
Signalling networks that regulate satellite cell activation and self-renewal – with particular emphasis on lipid and BMP pathways.
The satellite cell contribution to muscular dystrophies – how satellite cell dysfunction contributes to disease progression in Emery-Dreifuss muscular dystrophy, Facioscapulahumoural muscular dystrophy and Oculopharyngeal muscular dystrophy, amongst others.
The role of Pax genes – how Pax3 and Pax7 control satellite cells and their involvement in alveolar rhabdomyosarcoma.
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Lab interests include developmental genetics of muscle and its innervation in vertebrates, using zebrafish and mice; control of muscle cell size and character in the adult; comparative evolution of neuromuscular system; muscle repair in disease and after injury.
The specific project on offer this year involves analysis of the role of force in controlling the growth of zebrafish skeletal muscle. Two aspects can be investigated, depending on applicant's interest and ability:
A) The effect of specific applied forces on the growth of muscle. This project would suit a physiologist or physicist with aptitude for the design, construction and biological application of equipment to impose known forces on live zebrafish embryos and use force measurement and 4D confocal microscopy to analyse growth of muscle fibres and tissue.
B) The mechanisms by which muscle activity, and particularly force, regulates muscle stem cell functions, including proliferation, terminal differentiation and quiescence. The project would suit a cell biologist or physicist with interest in stem cell regulation, growth control and mechanobiology.
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CONTACTS FOR FURTHER INFORMATION
Professor Mathias Gautel, Dr Baljinder Mankoo