Science for Health
Limb defects are the second most common congenital abnormality present in human live births and diseases affecting the musculoskeletal system are a significant clinical problem, particularly in the older population. The goal of our work is to understand how the limbs form normally during embryogenesis and the genesis of limb abnormalities and diseases that affect the musculoskeletal system in humans.
Limbs are formed from specific regions of the flank of the embryo. At early stages of embryonic development, the forelimb and hindlimb buds are morphologically uniform and indistinguishable from one another. During subsequent steps of development however, dramatic changes take place. Each bud develops to form a network of interconnected limb elements -e.g. bones, muscles, and tendons-with morphologies characteristic of either the forelimb or hindlimb. We are using vertebrate animal models to understand the mechanisms that control the initiation of limb bud formation and the subsequent construction of the individual limb elements during embryonic development. A longer-term aim is to apply these findings to develop to potential therapeutic approaches that could contribute to maintenance and possible regeneration of these structures in later life.
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Confocal microscope image of the embryonic mouse forepaw, illustrating the interconnected network of muscle (red) and tendon (green) fibres. A dorsal view of the back of the hand and forearm is shown.
We use the developing limb as a model system using predominantly mouse and chick model organisms but also zebrafish and frog. In general our strategy is to interrogate gene function using a combination of coordinated gene misexpression and gene deletion experiments, often in more than one model system. In the mouse, we take advantage of gene conditional alleles and a repertoire of Cre deleter transgenics that we have developed ourselves or have collected. We often include transgene reporters to aid in phenotyping. In the chick, we are using genetic techniques to misexpress genes (either retroviral vectors or electroporation or direct application of recombinant proteins or substances) in combination with more classical embryological approaches. A new and important aspect of current and future work is to develop the use of in vitro techniques as an alternative, complementary approach to our in vivo models. Currently this involves the generation and characterisation of cell lines derived from transgenic reporter mouse lines we have produced and collected.
Limb deformities are a common abnormality found in humans. There are many examples of inherited disorders in which affected individuals carry a genetic mutation that causes abnormal limb development or where environmental factors have adversely affected limb development in the embryo (Thalidomide is a notorious example). Little is known, however, about how these genes and the pathways they regulate function normally during limb formation. Many genes that function during embryonic limb development are also required throughout life for normal limb tissue maintenance and repair. With an increasing proportion of the population surviving into old age, the number of people affected by age-related degenerative diseases of the limbs is increasing steadily. An important objective is therefore to understand the mechanism the regulate normal limb development and how disruption of these processes lead to diseases that affect the development or maintenance of limb elements so therapies to prevent or treat these conditions can be developed.
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