Our research projects


Our research focuses how intercellular signalling pathways act on musculoskeletal stem cells during zebrafish development. 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 during development and skeletal repair? 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

The opercle and hyomandibula bones stained pink.

Osteonectin and Collagen1. We have analysed how different signalling pathways regulate these steps during osteoblastogenesis using heatshock induction of signalling pathway components and pharmaceuticals that target individual pathways. Our work has shed light on how stem cells differentiate in vivo and may help to develop regenerative therapies for skeletal diseases such as osteoarthritis and osteoporosis. We have also found a link between osteoblast and adipocyte differentiation in vivo that may help us to unravel the genetic origins of diseases such as diabetes and obesity.


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. We have identified a novel role for the Ret signalling pathway during the development of a specific set of muscles which all connect to the opercle bone.

Immunolabelling shows the arrangement of slow (green) and fast (red) muscle fibres.

This analysis promises to elucidate how muscular and skeletal development are coordinated.


4 - Development of multilox technology in zebrafish. We have recently formed a UK-based consortium which aims to develop large numbers of Cre and Lox transgenic lines as a public resource to galvanise use of this technology in zebrafish. More information can be found on the ZCre website here.


Our research is primarily funded by the MRC and Cancer Research UK

 

Roehl Lab