Behavioural genetics: Beyond the body clock

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New research reveals novel roles for genetic components involved in Drosophila melanogaster circadian rhythms, indicating that these genes have diverse biological functions.

Two recent papers reveal new roles for genetic components of the Drosophila melanogaster body clock, indicating that these genes have diverse biological functions.

period (per) is crucial for regulating circadian rhythms in flies, and its expression requires CREB (cAMP-responsive element-binding protein), a transcription factor that is also essential for long-term memory (LTM). But does per also function downstream of CREB in LTM?

Sakai et al. addressed this question using a courtship assay to analyse the roles of per and CREB. A virgin male fly will try to copulate with a female who has already mated, but his advances will be rejected. After a while, he learns to court her less, and if the exposure time is long enough, LTM will be established.

The authors first showed that CREB is required for LTM in this assay. A form of CREB that has a repressive rather than an activating effect blocked the ability of the male to establish LTM. Mutation of per had a similar effect, whereas its overexpression enhanced LTM by reducing the exposure period needed.

As expected, per was found to act downstream of CREB in LTM, as overexpressing the repressive form of CREB had no effect on the enhanced LTM produced by per overexpression. Interestingly, the role of per in LTM seems to be independent of its function in generating circadian rhythms, as mutations in other key circadian genes had no effect on LTM.

In a second paper, Tsai and colleagues used a collection of P-element insertion lines to identify genes that are involved in cocaine responsiveness. One line with increased sensitivity contained an insertion in Lmo, a member of a family of genes with roles in neuronal development. The authors showed that one site of Lmo expression is in the ventral lateral neurons (LN_vs) — pacemaker cells that are essential for circadian rhythmicity in flies. Moreover, ectopic expression of wild-type Lmo in these cells was sufficient to rescue normal cocaine responsiveness in Lmo mutants.

So, is Lmo required for circadian activity and is this connected to the response to cocaine? The answer to the first question is 'yes', as circadian locomotor rhythms were disrupted in Lmo mutants. However, this was found to be independent of the role of Lmo in the cocaine response, which remains unaltered throughout the circadian cycle.

These studies reveal pleiotropic effects for genes that are involved in circadian rhythms, and this might well extend to other species. Unravelling the different molecular pathways that are involved in the distinct functions of these genes should prove an exciting direction for future work.

Louisa Flintoft

References

Sakai, T. et al. A clock gene, period, plays a key role in long-term memory formation in Drosophila . Proc. Natl Acad. Sci. USA 101, 16058–16063 (2004) | Article | PubMed |
Tsai, L. T. -Y. et al. Lmo mutants reveal a novel role for circadian pacemaker neurons in cocaine-induced behaviors. PLoS Biol. 2, 2122–2134 (2004) | Article |

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