ZEBRAFISH MYELIN

Analysis of myelinated axon development in zebrafish

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 Obiettivo del progetto (Objective)

'Myelinated axons are an essential component of the vertebrate nervous system. Myelin is a plasma membrane extension of specialised glial cells that wraps around axons to facilitate the rapid conduction of neuronal impulses. Disruption of myelinated axons contributes to the symptoms of numerous human diseases, such as Multiple Sclerosis (MS). Our understanding of the molecular and cellular mechanisms that co-ordinate myelin formation and those that contribute to the progression of human diseases of myelinated axons such as MS remain rudimentary. We have helped establish the zebrafish as a powerful laboratory organism with which to dissect myelin formation. Through a forward genetic screen we identified ten genes essential normal myelinated axon formation. We identified new roles for genes previously implicated in myelinated axon development, isolated two completely novel regulators and identified mutations in four genes relevant to human diseases of myelinated axons. Disruption to the human homologue of one of those genes, kif1b, was recently associated with MS, and our initial studies identified important roles for this protein in myelinated axon formation. In this proposal we ask for support to continue our analysis of kif1b function. Although our genetic screen was a success it did not approach saturation and additional screens would clearly identify other factors essential for myelinated axon development. Gene discovery screens, however, take a long time to carry out, are quite labour intensive and can preclude the identification of mutations in genes required for multiple stages of development. In this proposal we outline novel methodologies to identify protein function in biological processes of interest by combining high-throughput screening of the phenotypic effects of small molecules on zebrafish with cutting edge technology to identify the protein targets of compounds that exert interesting effects.'

Introduzione (Teaser)

A European research team used zebrafish as a model organism to investigate how neurons develop with a specialised cover known as myelin.

Descrizione progetto (Article)

Our body transmits information throughout the body along neurons. Electrical signals are sent down neuronal axons which are insulated on the outside with myelin to ensure rapid conduction of information. Myelin is a lipid-rich structure which extends from the plasma membrane of glial cells.

Disruption of myelin production leads to devastating neuronal conditions such as multiple sclerosis (MS). Although our body has the ability to repair damaged myelin, in degenerative conditions this process of remyelination fails. As a result, it is of paramount importance to study the molecular and cellular mechanisms that co-ordinate myelin formation in order to understand how loss of myelin progresses to disease development.

In this context, scientists on the EU-funded 'Analysis of myelinated axon development in zebrafish' (ZEBRAFISH MYELIN) project used zebrafish as a model for studying myelin formation. Zebrafish constitute an ideal model due to small size, transparency and rapid development, enabling researchers to observe biological events at high resolution.

Through a series of transgenic animals, scientists were able to manipulate myelination and visualise the outcome. They discovered that individual axons regulate myelin sheath production by oligodendrocytes over a very short time. The research team also successfully elucidated how myelin forms around neuronal axons and identified new genes and regulator molecules of the process of myelination.

The ZEBRAFISH MYELIN project findings have clinical implications as they will improve our understanding of neuronal degeneration in MS, culminating in the identification of novel therapeutic targets. The zebrafish model could also be used for the pharmacological screening of small molecules with therapeutic potential.