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Molecular and Cell Biology

Lab website address

Smith Laboratory Web Page

Short research description
Organisation and behaviour of chromosomes in plant meiosis

Full research description

Skeletal muscle stem cell biology and skeletal muscle disease
Skeletal muscle stem cells (SMSc) play an important role in the genesis of embryonic skeletal muscle and in the repair and restructuring of post-natal and adult skeletal muscles. SMSc can be isolated from mammalian skeletal muscles and may be induced to differentiate into skeletal muscle fibres both in vivo and in vitro. We are using this system to address important biological questions about the function and regulation of SMSc including (1) embryonic origin of SMSc (2) Molecular regulation of SMSc survival and apoptotic cell death. (3) the differentiation programme of SMSc. These processes are of relevance to two distinct groups of human disease: age-associated skeletal muscle atrophy and the skeletal muscle dystrophies. Much of our work has focussed on growth factor regulation of stem cell function in these diseases. We are currently investigating early myogenic events and aberrant stem cell function in the dystrophic mammal using a range of technologies including transgenesis and ShRNAi. We hope this work will lead to novel stem cell therapy and growth factor based therapeutic approaches for MD and muscle atrophy conditions.

 
Extended description:

Skeletal Muscle Dystrophies
(1) The mechanism of cell death in dystrophic skeletal muscle stem cells. Loss of or a defect in one or more of the components of the DGP leads to a number of severe congenital disease of the skeletal musclulature known collectively as Muscular Dystrophies (MD). The commonest form in humans is Duchenne Muscular Dystrophy (DMD) caused by mutation of Dystrophin. Apoptosis (cell death) of SMSc is a major early trigger of pathogenesis in MD. We identified a survival factor (Igf-2) which prevents cell death in skeletal muscle cells and normalises dystrophic pathology. We are investigating the mechanism of this interaction between Igf-2 and SMSc death and searching for molecules which could be used for clinical treatment of MD. Recently we established an embryonic basis for two forms of skeletal muscular dystrophy (MD); Duchenne MD and caveolin-3 deficiency type Limb Girdle MD (1c). We are currently investigating the molecular mechanisms which underlie this pathology in order to understand the biological function of DGC proteins in the embryo and to identify novel therapeutic targets for MD.

(2) Stem cell and gene therapy. Skeletal muscle stem cells are a potential route for the delivery of therapeutic genes to MD muscles and may also serve as a ‘protein factory’ by which stem cells engineered to express deficient genes (for example Factor VIII). We are investigating ways of engineering and delivering these cells for therapeutic use.
Skeletal Muscle Ageing
This study involves comparing the stem cell behaviour of normal and a short-lived animal models with respect to their rates of apoptotic cell death, differentiation capability and growth. The aim of this purpose is to identify the mechanism by which skeletal muscle atrophies with age and to devise ways of treating this debilitating condition using stem cells.
Myogenesis (embryonic muscle development)

IGF-2 is an important embryonic growth factor with pleiotrophic roles. During embryogenesis it regulates the cell cycle gene p57kip2. IGF-2 is expressed in differentiating myotubes during myogeneis (embryonic skeletal muscle formation). We are studying the role of IGF-2 in embryonic skeletal muscle development and are examining the role of the embryonic skeletal muscle stem cell (eSMSc) in culture and in vitro. In particular we are looking for gene markers of eSMSc which will enable us to identify them and track their progress.

Merrick, D., Chen, H., Larner, D., Smith, J., Adult and Embryonic Skeletal Muscle Microexplant Culture and Isolation of Skeletal Muscle Stem Cells. http://www.jove.com/details.php?id=2051 doi: 10.3791/2051. J Vis Exp. 43 (2010).

Merrick D, Stadler LKJ, Larner, DP & Smith J. (2009). Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation. Disease Models & Mechanisms 2, 374-388

Smith, J. & Merrick, D (2010). Embryonic skeletal muscle micro-explant culture and isolation of skeletal muscle stem cells. In: A. Ward, D. Tosh (eds.), Mouse Cell Culture, Methods in Molecular Biology 633, Springer Science+Business Media, LLC 2010

Smith, J and others. Biology’s grammarian: Darwin’s dangerous idea today. THES 6th February, 2009

Additional articles written for the Times Higher Education Supplement (THES) by Janet Smith can be found on

www.timeshighereducation.co.uk

Stadler LKJ, Merrick D & Smith J. (2008) Morphological, stem cell and fast myosin abnormalities in the cav-3-/- and mdx dystrophic embryo reveal an embryonic basis for muscular dystrophy Genetical Research 90:281-289.

Merrick D, Ting T, Stadler LKJ & Smith J (2007) A role for Insulin-like growth factor 2 in specification of the fast skeletal muscle fibre. BMC Developmental Biology, 7:65

Foreman MA, Smith J, Publicover SJ.(2006). Characterisation of serum-induced intracellular Ca2+ oscillations in primary bone marrow stromal cells. J Cell Physiol. 206, 664-71.

Skeletal muscle and stem cells

Foreman MA, Smith J, Publicover SJ (2006). Characterisation of serum-induced intracellular Ca2+ oscillations in primary bone marrow stromal cells. J Cell Physiol.206, 664-71.

Smith J, Rao AK & O’Shea L Age associated skeletal muscle atrophy : an accelerated model. 4th European Congress of Biogerontology, Newcastle upon Tyne, UK: 7-10th November, 2004.

Smith J (2004). Skeletal muscle atrophy in ageing mice : an accelerated model. Ageing cell : Ageing body, BSRA summer meeting: 14th July, 2004, University of Birmingham

Toora M., Merrick D, Rao A. & Smith, J. (2003). “Stem cells, skeletal muscle and the mammalian ageing processâ€. Proc. Indian Natn. Sci. Acad. B69: 191-208.

Toora M, Rao AK, Smith J Skeletal muscle stem cell function during ageing: death, differentiation and division. BBSRC ERA Initiative Workshop, 14-15th January, 2003.

Rao AK, O’ Shea L, Johnson C, Rooney M & Smith J The role of the stem cell in skeletal muscle ageing. BBSRC SAGE/ERA Initiatives Workshop, 14-15th January, 2002.

Rao AK, O’Shea L, Johnson C, Smith J Adult stem cells and mammalian ageing. Abstract 413. Keystone Symposium on ‘Stem cells: Origins, Fates and Functions’, March 17-23, 2002. Keystone resort, Keystone, Colorado, USA.

Rao AK, O’ Shea L, Johnson C, Rooney M, Smith J The role of the stem cell in skeletal muscle ageing. Abstract P97. First Conference on Functional Genomics of Ageing, April 24-27, 2002: Melia Lebreros Hotel, Seville, Spain.

O’Shea L, Johnson C, Rooney M, Gleeson R, Woods K & Smith J (2001) Adipogenesis and skeletal muscle ageing Mech. Ageing Devel. 122,1354-5.

Marrone A, Sims L & Smith J Growth control in skeletal muscle stem cells. (2000) 18th International conference of Biochemistry and Molecular biology, Beyond the Genome. Birmingham, UK 16th :20th July. 18th IUMB abstract, 1372.

Toora M, Rao AK & Smith J Is apoptosis important in skeletal muscle ageing? Abstract P-130.10th Euroconference on Apoptosis, ‘Charming to death’, 11-13th October, 2002; Institut Pasteur, Paris, France.[Conference Abstract]

D. Merrick, I Badr, M Watkins, J. Smith. (2002). IGF-2 function in skeletal muscle differentiation. Edited by AJ Copp & EMC Fisher. Genet. Res. Camb. 80, 63-75.

Toora M, Rao AK & Smith J Is apoptosis important in skeletal muscle ageing? Abstract P-130.10th Euroconference on Apoptosis, ‘Charming to death’, 11-13th October, 2002; Institut Pasteur, Paris, France.[Conference Abstract]

Ting T, Zeng J, Marrone A & Smith J The contribution of apoptosis to skeletal muscle disease : can survival factors be used to treat muscular dystrophy? Abstract P-129.10th Euroconference on Apoptosis, ‘Charming to death’, 11-13th October, 2002; Institut Pasteur, Paris, France.[Conference Abstract]

O’Shea L, Johnson C, Rooney M, Gleeson R, Woods K & Smith J (2001) Adipogenesis and skeletal muscle ageing Mech. Ageing Devel. 122,1354-5.

Smith J, Goldsmith C, Ward A & LeDieu, R (2000) IGF-II ameliorates the dystrophic phenotype and coordinately down-regulates programmed cell death. Cell Death and Diff. 7, 1109-1118.

Woods, K., Marrone, A. & Smith, J (2000) Programmed cell death and senescence in skeletal muscle stem cells. Ann. Proc. Natl. Acad. Sci 908, 331-335.

Smith J, Ward A, Goldsmith C, De Haas van Dorsser F & Le Dieu R. (2000) IGF-II ameliorates the dystrophic phenotype. Genetical Research 76, 199-214.

Marrone A, Sims L & Smith J Growth control in skeletal muscle stem cells. (2000) 18th International conference of Biochemistry and Molecular biology, Beyond the Genome. Birmingham, UK 16th :20th July. 18th IUMB abstract, 1372.

Woods, K & Smith, J. Programmed cell death and senescence in skeletal muscle stem cells. 18th-22nd September, 1999. EMBO Workshop on Molecular and Cellular gerontology, Serpiano, Ticino, Switzerland.

Granerus, M., Bierke, P., Zumkeller, W., Smith, J., Engstrom, W., and Schofield, P. N. (1995). Insulin-like growth factors I and II prevent apoptosis in a human teratoma derived cell line. J. Clin. Pathol.: Mol. Pathol. 48 , 153-157.

Smith, J. (1994). Therapeutic effects of IGF-2 on dystrophic skeletal muscle. Growth Regulation 4, 61-62

Schofield, P. N., Smith, J., Parkin, M., Dellow, R., Mahmood, A., Zumkeller, W., Morrell, D., Moran, I, Ekstrom, T., Nystrom, A. & Ohlsson, R. (1994). Insulin-like growth factor II in the control of developmental tumour and embryonic stem cell growth. In : Frontiers in Endocrinology Volume 6, Developmental Endocrinology (Eds. P. C. In Sizonenko, M. L. Aubert & J-D. Vassalli), Ares-Serono Symposia , Rome, Italy. Pp 213-218.

Smith, J, & Hooper, M. L. (1989). Dominance and independent segregation of metabolic cooperation - competence and pluripotency in an embryonal carcinoma cell hybrid. Exp. Cell Research, 181, 40-50.

Muscular Dystrophy

Merrick D, Badr I, Watkins M & Smith J (2002). IGF-2 function in skeletal muscle differentiation. Edited by AJ Copp & EMC Fisher. Genet. Res. Camb. 80, 63-75.

Smith J, Ward A, Goldsmith C, De Haas van Dorsser F & Le Dieu R. (2000) IGF-II ameliorates the dystrophic phenotype. Genetical Research 76, 199-214.

Merrick D, Ting T & Smith J (2005). Evidence for a role in skeletal muscle fibre type selection. Conference proceedings, edited by AJ Copp & EMC Fisher. Genet. Res. Camb. Genetical Research 86, 233-241

Merrick D, Ting T & Smith J (2004) A role for Igf-2 in fibre-type selection: Insulin-like Growth Factor II (Igf-2) promotes the formation of fast myosin positive myotubes. Conference proceedings, edited by AJ Copp & EMC Fisher. Genet. Res. Camb. 84, 1-12

T. Ting & J. Smith. (2003) Muscle specific expression of Igf-2 and GFP in dystrophic mice. Edited by AJ Copp & EMC Fisher. Genet. Res. Camb. 81, 229-241.

Merrick D & Smith J IGF-2 and skeletal muscle stem cell differentiation. BBSRC workshop: Epigenetic Mechanisms regulating developmental plasticity. 7-8th May, 2002, Robinson College Executive Centre, Wyboston, Nr Cambridge, UK.

Ting T & Smith J (2002). Muscle specific expression of Igf-2 in dystrophic mice. HUGO Genetics Meeting 2002, Shanghai, China.

Woods, K & Smith, J. Programmed cell death and senescence in skeletal muscle stem cells. 18th-22nd September, 1999. EMBO Workshop on Molecular and Cellular gerontology, Serpiano, Ticino, Switzerland.

Ting T, Zeng J, Marrone A & Smith J The contribution of apoptosis to skeletal muscle disease : can survival factors be used to treat muscular dystrophy? Abstract P-129.10th Euroconference on Apoptosis, ‘Charming to death’, 11-13th October, 2002; Institut Pasteur, Paris, France.[Conference Abstract]

Smith, J. & Schofield, P. N. (1997) Stable integration of an mdx skeletal muscle cell line into dystrophic (mdx) skeletal muscle: evidence for stem cell status. Cell Growth and Differentiation 8, 927-934.

Smith, J. (1996). Muscle Growth factors, ubiquitin and apoptosis in dystrophic muscle: Apoptosis declines with age in the mdx mouse. B. Appl. Myol. 6, 279-284.

Smith, J. Fowkes, G. & Schofield, P. N. (1995). Programmed cell death in dystrophic (mdx) muscle is inhibited by IGF-II. cellDeath & Differentiation 2, 243-251.

Smith, J. & Schofield, P.N. (1994). The effects of fibroblast growth factors in long term primary culture of dystrophic (mdx) mouse muscle myoblasts. Experimental Cell Research 210, 86-93.

Developmental pattern and growth

Westbury J, Watkins M, Ferguson-Smith AC & Smith J (2001) Dynamic regulation of the cdk inhibitor p57kip2 during embryo morphogenesis. Conference proceedings, edited by AJ Copp & EMC Fisher. Genetical Research 78, 191-206.

Wesbury J, Watkins M, Ferguson-Smith AC, and Smith, J. (2001) Dynamic and temporal regulation of the cdk inhibitor P57kip2 during embryo morphogenesis. Mechanisms of Development 109: 83-89.

Westbury J, Watkins M, Ferguson-Smith AC & Smith J (2000) P57kip2 exhibits a dynamic and temporally regulated expression pattern during embryonic morphogenesis. International conference of Biochemistry and Molecular biology, Beyond the Genome. Birmingham, UK 16th :20th July. Abst. No. 1389.

Grandjean, V, Smith, J, Watkins, M & Ferguson-Smith, A.C. (2000). Increased IGF-II protein affects P57kip2 expression in vivo and in vitro: implications for Beckwith-Weidemann syndrome. Proc. Natl. Acad. Sci. (USA) 97, 5279-5284.

Westbury J, Watkins M, Ferguson-Smith AC & Smith J (2000) P57kip2 exhibits a dynamic and temporally regulated expression pattern during embryonic morphogenesis. International conference of Biochemistry and Molecular biology, Beyond the Genome. Birmingham, UK. Abst. No. 1389.

Smith, J. & McLachlan, J. C. (1990). Identification of a novel growth factor with transforming activity secreted by individual chick embryos. Development 109. 905-910.

Smith, J. & McLachlan, J. C. (1989). Developmental pattern of growth factor production in chick embryo limb buds. J. Of Anat. 165. 159-168.

Macintyre, J., Hume, D. D., Smith, J & McLachlan, J.C. (1988). A microwell assay for anchorage independent growth. Tissue and Cell 20, 331-338.

McLachlan, J. C., Macintyre, J., Hume, D. D., & Smith, J. (1988). Direct demonstration of production of transforming growth factor activity by embryonic chick tissue. Experientia 44. 351-352.

Human disease and growth factors

Baillie, R., Coombes, R.C. & 1 Inβ−Smith, J. (1996). Multiple Forms of TGF Breast Tissues: a biologically active form of the small latent complex . The European Journal of Cancer 32, 1566-1573.1βof TGF-

Schofield, P. N., Nystrom, A., Smith, J., Spitz, L., Grant, D., and Zapf, J., (1995). Expression of a high molecular weight form of IGF-11 in a Beckwith -Weidemann syndrome associated adrenocortical adenoma. Cancer Letters 94, 71-77.

Smith, J., Baillie, R.,Yelland,A., & Coombes, R.C. (1994). Acidic and basic fibroblast growth factors in human breast tissue. The European Journal of Cancer 30, 496-503.

Smith, J., Baillie, R., Chander, S. K., & Coombes, R. C. (1993). The effect of endocrine therapy on acidic FGF-like activity in NMU rat mammary tumours. The European Journal of Cancer 29, 2125-2131.

Schofield, P. N., Zumkeller, W., Smith, J., Morrell, D. J., Brice, A. L., Engstrom, W. & Dellow, R. (1993). Role of growth factors in human development: Insulin-like growth factor II. Pp. 211-217. In: Progress In Endocrinology ed. R. Mornex, C. Jaffiol & J. Leclere. Parthenon Press.

Lugmani, Y.A., Smith, J. & Coombes, R.C. (1992). Polymerase chain reaction-aided analysis of gene expression in frozen tissue sections. Analytical Biochemistry 200, 291-295.

Gomm, J. J., Smith, J., Ryall, G. K., Baillie, R., Turnbull, L. & Coombes, R.C. (1991). The localisation of basic fibroblast growth factor and transforming growth factor Bl in the human mammary gland. Cancer Research 51, 4685-4692.

Smith, J., Gomm, J. J., Baillie, R., Chander, S. K. & Coombes, R. C. (1990). Growth factor secretion and endocrine control in breast cancer. Proceedings of the American Association for Cancer Research, 189-91.

Smith, J., Chander, S.K. Baillie, R., Gomm, J.J. & Coombes, R.C. (1990). Growth factor secretion and endocrine control in NMU rat mammary carcinoma. J. Cancer Research & Clinical Oncology 116 supplement (1), 487.

Gomm, J.J., Smith, J., Ricketts, D.M., Ryall, G.K., Turnbull, L. & Coombes, R.C. (1990). The immunohistochemical localisation of growth factors in the normal human breast. J. Cancer Research & Clinical Oncology 116 supplement (1), 325.