Projects

Gene Function and Expression in Drosophila Muscle and Heart Differentiation

Drosophila muscles.

Our research interest is focussed on how cells become different from each other and develop into specialised tissues. Current research centres on the conserved transcription factor Mef2 and a small number of novel genes that we uncovered in a screen for genes specifically expressed during mesoderm differentiation.

We analyse both their function and control of expression during muscle and heart development. We work with the fruit fly Drosophila melanogaster, a model organism with many advantages for molecular and genetic analyses of development. Historically studies in Drosophila have shaped a lot of our understanding of many aspects of biology. We study cell differentiation, not only because of the fascination of how an egg develops into a free-living animal, but also because of more applied considerations. These include stem cells, where a thorough knowledge of differentiation is necessary to both monitor and manipulate their differentiation, and cancer biology, where differentiation and proliferation are two sides of the same coin.

In situ hybridisation of a novel gene we have identified showing expression in individual Adult Muscle Precursor cell.

A novel inhibitor of muscle differentiation

In muscle, although some molecules are implicated in negative regulation, there has been little in vivo evidence. However, we have recently discovered a novel inhibitor of larval muscle differentiation that down-regulates Mef2 activity. This work has revealed a balance of positive and negative inputs controlling muscle differentiation during Drosophila development. We are now analysing this differentiation switch that could hold cells in a committed, but undifferentiated state, in both larval muscle development and in some adult muscles, which are remodeled during metamorphosis in a type of regeneration.

Analysis of Mef2 function in muscle differentiation

Mef2 is the crucial positive regulator of muscle differentiation and recent work suggests it has hundreds of target genes, which have different temporal patterns of gene expression. A major question is how does Mef2, a single transcription factor, co-ordinate the expression of such a large number of target genes. We are addressing this using a combination of microarrays and Drosophila genetics and have recently uncovered genes that require different levels of Mef2. We are now analyzing them to understand this aspect of muscle differentiation.

Analysis of gene expression in heart and muscle development

A thorough understanding of development requires an understanding of cell-type specific gene expression. We study this issue in both heart and muscle through making promoter/enhancer constructs linked to reporter genes and assaying in vivo using confocal microscopy to monitor gene expression on a cell-by-cell basis. The approach is accelerated by using "phylogenetic footprinting" to identify evolutionarily conserved, and hence probably functionally important, regions. The heart is an excellent example to address how the patterning events that control early development are interpreted to produce diverse cell types as it has genetically distinct cells identifiable by markers organised in a simple pattern.

Function and expression of other genes

We are analyzing other novel genes from our screen. One is a Mef2 target that may direct muscle precursor migration. A second encodes a protein implicated in signal transduction. We also analyse genes that are potential Hox targets. Mutations in one, implicated in RNA processing, show a link to cell growth. Additional opportunities for new research directions are provided by the lab's membership of an EU FP6 Network of Excellence "MYORES".

Concluding remarks

Studies in Drosophila are likely to be significant for human biology. This is suggested both by the finding that 60% of fly genes have human counterparts and by the conservation of many molecular mechanisms of muscle and heart development between Drosophila and other species. Moreover, there are similar genes in Drosophila for nearly 80% of human "disease genes". Prospective post-doctoral fellows or PhD students interested in our work are encouraged to contact the lab.

Grants

• BBSRC
• EU FP6 Network of Excellence "MYORES"
• John Ryder Memorial Trust

Research group members

Ms Jun Han

Postgraduate research students 

Miss Alina Cepraga

Collaborations

• Dr Eileen Furlong, Heidelberg, Germany.
• Dr Zhe Han, Ann Arbor, USA
• Dr Krzysztof Jagla, Clermont-Ferrand, France.
• Prof Eric Olson Dallas, USA.