Department of Biochemistry University of Oxford Department of Biochemistry
University of Oxford
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Oxford OX1 3QU

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Worm points researchers in the right direction

Dr Andreas Russ, University Lecturer in the Biochemistry Department, is on a quest - to pin down the function of genes in the human genome which are potential targets for drug development.

His latest project, on a gene called latrophilin, has taken him on a journey that involves worm embryos, Attention-deficit hyperactivity disorder (ADHD), and, most unexpectedly of all, the toxin from the Black Widow Spider.

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The early stage worm embryo. Components of the cell division machinery are tagged with a fluorescent marker so that individual cells can be traced during development

Dr Russ and his group in the department, together with colleagues in Germany, Japan, and the States, have published their findings in Developmental Cell.1

Dr. Russ works on so-called 'orphan genes' - genes that have been identified by genome sequencing but for which there is little or no information about how they work and whether they might be used for pharmaceutical development.

Some of these orphan genes belong to a large gene family which codes for proteins known as GPCRs (G Protein-Coupled Receptors). GPCR proteins sit in the cell membrane and have external and internal portions. They sense molecules outside the cell and relay a signal to the cell's interior.

'What we've come up with is a new biological mechanism - how to align cells as the embryo develops.'

The family has become a focus for drug development because some of its members are known to be involved in disease. Around half of all drugs target a GPCR protein, including those widely used to treat conditions such as allergies, heart disease and psychiatric disorders.

Only a small fraction of the GPCR genes in the genome, though, are currently targeted by medicines. 'GPCR genes like latrophilin look like existing drug targets, but to predict their medical potential we have to understand their function first,' says Dr Russ.

Until now, the only biology linked to latrophilin was the preserve of neurobiologists. This is where the Black Widow Spider comes into the story. The neurotoxin from this venomous spider paralyses prey by binding to the latrophilin receptor and sending nerve cell communication first into overdrive and then into breakdown.

'It was generally thought that latrophilin receptors would be modulating nerve cell activity which made them attractive drug targets for neuropsychiatric diseases,' explains Dr Russ. 'But this had not been unambiguously tied down by experiments.'

In normal worm embryos, cells align in a head-to-tail direction (white arrows). In mutant embryos lacking lat-1, cells normally destined to form head structures do not align the right way (yellow arrow), disrupting development. Components of the cell division machinery are tagged with a fluorescent marker

In normal worm embryos, cells align in a head-to-tail direction (white arrows). In mutant embryos lacking lat-1, cells normally destined to form head structures do not align the right way (yellow arrow), disrupting development. Components of the cell division machinery are tagged with a fluorescent marker

Latrophilin genes are highly conserved across all animals and are even found in those with a very simple nervous system. So Dr Russ and his colleagues turned to the nematode worm, Caenorhabditis elegans, to investigate the gene's function further.

C. elegans is particularly popular with developmental biologists because its embryos are transparent. Researchers are therefore able to track the fate of individual cells.

The researchers used a mutant form of C. elegans that lacks a functional latrophilin gene (lat-1). Most of the embryos die from developmental defects and some lack head structures. Surprisingly, those that survive are not paralysed.

The results of Dr Russ and colleagues pointed to a different and unexpected function for latrophilin.

'What we found was that latrophilin is not essential for neuronal function, but it is essential to build the very early body plan of the embryo. When we looked closer at our worms, we noticed that some cells were not pointing in the right direction. They are not getting in line with their neighbours, but break ranks and divide sideways.'

During development, cells undergo precisely orchestrated movements so that the right body structure and organs form. They rely on molecular signals to instruct them where in the embryo they should be and what specialised cell type they should develop into.

'It's well established how cells get their 'postcode' - where they are along an axis,' says Dr Russ. 'But much less is known about how they know which way the 'traffic is going along the street'. That determines the polarity of the whole structure. An individual cell has to know which way to point. What we've come up with is a new biological mechanism - how to align cells as the embryo develops.'

A ball model of the worm embryo. Different cell groups are colour-coded and traced during development. In mutant embryos lacking lat-1, cell groups lose their sense of direction and mix with the wrong crowd

A ball model of the worm embryo. Different cell groups are colour-coded and traced during development. In mutant embryos lacking lat-1, cell groups lose their sense of direction and mix with the wrong crowd

In the mutant, the signal responsible for lining the cells up is established as normal but is then not transmitted correctly in the sheet of cells. 'The main contribution of our work is towards understanding how the polarity at the simple 4-cell stage is propagated as the embryo develops a few hours later to 1000 cells that still align.'

Latrophilin is still very likely to have a role in the nervous system, but may act in a different way from previously assumed. Dr Russ has evidence that it is involved in a process called axon guidance which wires up the nervous system. This is another form of cell polarity which determines the direction of growth of an axon, the long slender projection from a nerve cell that conducts electrical impulses.

An involvement in wiring up the nervous system might explain a possible intriguing link between latrophilin and a common behavioural disorder in children.

'There have been preliminary reports that one human version of latrophilin may be contributing to ADHD. We have to be very cautious here, as the groups working on this haven't published it yet. But what we have found out about latrophilin function would make a lot of sense in this context.'

Dr. Russ and his colleagues expect to learn a lot more from C. elegans about latrophilin's function. 'Latrophilin and related receptors are still much less well understood than other GPCRs,' says Dr Russ. ''We've been struggling to get a good experimental handle on their functions. Now we have a powerful genetic system to see how they work in their natural context.'

  1. Langenhan, T., Promel, S., Mestek, L., Esmaeli, B., Waller-Evans, H., Hennig, C., Kohara, Y., Avery, L., Vakonakis, I., Schnabel, R., and Russ, A. P. Latrophilin signalling links anterior-posterior tissue polarity and oriented cell divisions in the C. elegans embryo. Dev Cell 17, 494-504, (2009)

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