ZFIN ID: ZDB-PERS-960805-468
||Centre for Developmental and Biomedical Genetics
Department of Biomedical Sciences
University of Sheffield
Firth Court, Western Bank
South Yorkshire, S10 2TN
||Office: 44-114-22-22351, Lab: 44-114-22-22376
BIOGRAPHY AND RESEARCH INTERESTS
Skeletal diseases such as arthritis, osteoporosis and bone tumours affect millions of people worldwide. Researchers hope to use regenerative medicine to repair the damage caused by these diseases in the future. One of our research focuses is on the genetic regulation of skeletal development in zebrafish. Although zebrafish are a small tropical fish, we now know that the skeleton develops in much the same way as in humans. We hope that by understanding how the skeleton is generated in zebrafish, we will provide information on how to regenerate the skeleton in human patients.
One disease which our research has already shed light on is called Hereditary Multiple Exostoses. Hereditary Multiple Exostoses causes the formation of benign bone tumours in children. Besides causing severe skeletal deformity, the bone tumours can compress nerves or other tissue resulting in chronic pain. Although the tumours can usually be surgically removed, they sometimes recur, or are in positions that prevent surgery. We have identified two strains of zebrafish whose offspring have skeletal defects that resemble those of patients with Hereditary Multiple Exostoses.
We have found that each strain carries a mutated form of an essential gene. Importantly, these two genes are also found in humans and thus by analysing their function in zebrafish we may shed light on their role in humans. Our study has elucidated the roles of these genes during normal skeletal development and has allowed us to generate a model for how genetic changes give rise to bone tumours in humans.
Our research focuses on the role of intercellular signalling pathways during musculoskeletal skeletal development in zebrafish. We have three projects ongoing in our group:
1 - What is the role of heparin sulphate proteoglycans (HSPGs) during skeletogenesis? Although HSPGs are ubiquitous structural components of the extracellular matrix, they are also thought to play very specific roles in cell-cell signalling during development. We found that two zebrafish lines carry mutations in ext2 and papst1, two genes that are essential for the synthesis of HSPGs. Using these lines we have shown that HSPGs are not required for chondrocyte differentiation, but are required during cartilage morphogenesis and hypertrophy. We have also found that osteoblast differentiation requires HSPGs. Our results help to shed light on the aetiology of a disease called multiple osteochondromas which is caused by mutations in human ext2.
2 - How do developmental signalling pathways regulate osteoblast differentiation? Osteoblasts in zebrafish follow the same differentiation pathway as in mammals: The runx2 genes are expressed in early skeletal precursors, followed by osterix and then finally by genes encoding bone proteins such as osteonectin and collagen1. We have begun to analyse how different signalling pathways regulate these steps during osteoblastogenesis using heatshock induction of signalling pathway components and pharmaceuticals that target individual pathways.
3 - Which signalling pathways regulate skeletal muscle development? Very little is known about how individual muscles know where to attach to the skeleton. We have been analysing a set of mutants that affect specific muscles while leaving other muscles and the underlying skeleton unaffected. This analysis promises to elucidate how muscular and skeletal development are coordinated.
Dyer, C., Blanc, E., Hanisch, A., Roehl, H., Otto, G.W., Yu, T., Basson, M.A., and Knight, R. (2014) A bi-modal function of Wnt signalling directs an FGF activity gradient to spatially regulate neuronal differentiation in the midbrain. Development (Cambridge, England). 141(1):63-72
Gray, C., Bratt, D., Lees, J., Dacosta, M., Plant, K., Solaymani-Kohal, S., Tazzyman, S., Serbanovic-Canic, J., Crossman, D.C., Keavney, B.D., Haase, A., McMahon, K., Gering, M., Roehl, H., Evans, P.C., and Chico, T.J. (2013) Loss of Function of Parathyroid Hormone Receptor 1 Induces Notch-Dependent Aortic Defects During Zebrafish Vascular Development. Arterioscler. Thromb. Vasc. Biol.. 33(6):1257-63
Thompson, M.J., Louth, J.C., Ferrara, S., Jackson, M.P., Sorrell, F.J., Cochrane, E.J., Gever, J., Baxendale, S., Silber, B.M., Roehl, H.H., and Chen, B. (2011) Discovery of 6-substituted indole-3-glyoxylamides as lead antiprion agents with enhanced cell line activity, improved microsomal stability and low toxicity. European Journal of Medicinal Chemistry. 46(9):4125-32
Sousa, S., Afonso, N., Bensimon-Brito, A., Fonseca, M., Simões, M., Leon, J., Roehl, H., Cancela, M.L., and Jacinto, A. (2011) Differentiated skeletal cells contribute to blastema formation during zebrafish fin regeneration. Development (Cambridge, England). 138(18):3897-3905
Knight, R.D., Mebus, K., d'Angelo, A., Yokoya, K., Heanue, T., and Roehl, H. (2011) Ret signalling integrates a craniofacial muscle module during development. Development (Cambridge, England). 138(10):2015-2024
Clément, A., Wiweger, M., von der Hardt, S., Rusch, M.A., Selleck, S.B., Chien, C.B., and Roehl, H.H. (2008) Regulation of zebrafish skeletogenesis by ext2/dackel and papst1/pinscher. PLoS Genetics. 4(7):e1000136
Laue, K., Daujat, S., Crump, J.G., Plaster, N., Roehl, H.H., Tübingen 2000 Screen Consortium, Kimmel, C.B., Schneider, R., and Hammerschmidt, M. (2008) The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity. Development (Cambridge, England). 135(11):1935-1946
Lee, J.S., von der Hardt, S., Rusch, M.A., Stringer, S.E., Stickney, H.L., Talbot, W.S., Geisler, R., Nüsslein-Volhard, C., Selleck, S.B., Chien, C.B., and Roehl, H. (2004) Axon Sorting in the Optic Tract Requires HSPG Synthesis by ext2 (dackel) and extl3 (boxer). Neuron. 44(6):947-960
Herzog, W., Sonntag, C., Von Der Hardt, S., Roehl, H.H., Varga, Z.M., and Hammerschmidt, M. (2004) Fgf3 signaling from the ventral diencephalon is required for early specification and subsequent survival of the zebrafish adenohypophysis. Development (Cambridge, England). 131(15):3681-3692
Ulrich, F., Concha, M.L., Heid, P.J., Voss, E., Witzel, S., Roehl, H., Tada, M., Wilson, S.W., Adams, R.J., Soll, D.R., and Heisenberg, C.P. (2003) Slb/Wnt11 controls hypoblast cell migration and morphogenesis at the onset of zebrafish gastrulation. Development (Cambridge, England). 130(22):5375-5384
Geisler, R., Rauch, G.J., Baier, H., van Bebber, F., Brobeta, L., Dekens, M.P., Finger, K., Fricke, C., Gates, M.A., Geiger, H., Geiger-Rudolph, S., Gilmour, D., Glaser, S., Gnugge, L., Habeck, H., Hingst, K., Holley, S., Keenan, J., Kirn, A., Knaut, H., Lashkari, D., Maderspacher, F., Martyn, U., Neuhauss, S., Neumann, C., Nicolson, T., Pelegri, F., Ray, R., Rick, J.M., Roehl, H., Roeser, T., Schauerte, H.E., Schier, A.F., Schönberger, U., Schönthaler, H.-B., Schulte-Merker, S., Seydler, C., Talbot, W.S., Weiler, C., Nüsslein-Volhard, C., and Haffter, P. (1999) A radiation hybrid map of the zebrafish genome. Nature Genetics. 23(1):86-89
Roehl H and Pacifici M
Sugars, bones and a disease called Multiple Hereditary Exostoses.
Developmental Dynamics. 2010 239(6) 1901-1904