A fly's eye view of biology.

Determining how genes function in developmentally complex multicellular organisms can be a formidable task. Obstacles arise from the fact that inactivation of most genes results in subtle or undetectable phenotypic alterations, and when phenotypes are observed they are often difficult to interpret because most genes play multiple roles in development. New techniques that have been applied to studying genes in the developing Drosophila eye promise to circumvent these obstacles. The advent of these techniques combined with the existing wealth of information about cellular pattern formation in the Drosophila eye make the eye a powerful model system for deciphering the function of genes in biological processes.     

Neurobiology of the fruit fly's circadian clock

Studying the fruit fly Drosophila melanogaster has revealed mechanisms underlying circadian clock function. Rhythmic behavior could be assessed to the function of several clock genes that generate circadian oscillations in certain brain neurons, which finally modulate behavior in a circadian manner. This review outlines how individual circadian pacemaker neurons in the fruit fly's brain control rhythm in locomotor activity and eclosion.     

Spam and the evolution of the fly's eye

The open rhabdoms of the fly's eye enhance absolute sensitivity but to avoid compromising spatial acuity they require precise optical geometry and neural connections.1 This neural superposition system evolved from the ancestral insect eye, which has fused rhabdoms. A recent paper by Zelhof and co-workers shows that the Drosophila gene spacemaker (spam) is necessary for development of open rhabdoms, and suggests that mutants revert to an ancestral state. Here I outline how open rhabdoms and neural superposition may have evolved via nocturnal intermediates, and discuss the implications for the role of spam in insect phylogeny.     

Loss of eye movements abolishes light entrainment of circadian mesolimbic catecholamine excitability: A function for REM?

Light entrainment of the circadian rhythm of mesolimbic dopamine excitability, measured by the amphetamine-induced locomotor response, and the circadian feeding rhythm was abolished following section of the extraocular muscles of the rat. Endogenous (free-running) circadian rhythms were preserved. The results are consistent with electrophysiologic evidence that the rapid eye movements during paradoxical sleep transmit light-modulated electrical potentials to regions of the brain that influence circadian rhytms and dopamine release.     

Serotonin modulates circadian entrainment in Drosophila

Entrainment of the Drosophila circadian clock to light involves the light-induced degradation of the clock protein timeless (TIM). We show here that this entrainment mechanism is inhibited by serotonin, acting through the Drosophila serotonin receptor 1B (d5-HT1B). d5-HT1B is expressed in clock neurons, and alterations of its levels affect molecular and behavioral responses of the clock to light. Effects of d5-HT1B are synergistic with a mutation in the circadian photoreceptor cryptochrome (CRY) and are mediated by SHAGGY (SGG), Drosophila glycogen synthase kinase 3beta (GSK3beta), which phosphorylates TIM. Levels of serotonin are decreased in flies maintained in extended constant darkness, suggesting that modulation of the clock by serotonin may vary under different environmental conditions. These data identify a molecular connection between serotonin signaling and the central clock component TIM and suggest a homeostatic mechanism for the regulation of circadian photosensitivity in Drosophila.     

A wormer's eye view

A report on the thirteenth international Caenorhabditis elegans meeting, University of California, Los Angeles, USA, 22-26 June 2001.     

Phase sensitivity analysis of circadian rhythm entrainment

As a biological clock, circadian rhythms evolve to accomplish a stable (robust) entrainment to environmental cycles, of which light is the most obvious. The mechanism of photic entrainment is not known, but two models of entrainment have been proposed based on whether light has a continuous (parametric) or discrete (nonparametric) effect on the circadian pacemaker. A novel sensitivity analysis is developed to study the circadian entrainment in silico based on a limit cycle approach and applied to a model of Drosophila circadian rhythm. The comparative analyses of complete and skeleton photoperiods suggest a trade-off between the contribution of period modulation (parametric effect) and phase shift (nonparametric effect) in Drosophila circadian entrainment. The results also give suggestions for an experimental study to (in)validate the two models of entrainment.     

Asymmetric localization and function of cell-fate determinants: a fly's view

One mechanism to generate daughter cells with distinct fates is the asymmetric inheritance of regulatory proteins, leading to differential gene regulation in the daughter cells. This mode of cell division is termed 'asymmetric cell division.' The nervous system of the fly employs asymmetric cell division, both in the central nervous system, to generate neural precursors, neurons and glial cells; and in the peripheral nervous system, to create sensory organs that are composed of multiple cell types. These cell lineages are excellent models to examine the gene expression program that leads to fate acquisition, the cell-fate determinants that control these programs and how these determinants, in turn, are distributed through cell polarity machinery.     

Extraocular photoreception and circadian entrainment in nonmammalian vertebrates

In mammals both the regulation of circadian rhythms and photoperiodic responses depend exclusively upon photic information provided by the lateral eyes; however, nonmammalian vertebrates can also rely on multiple extraocular photoreceptors to perform the same tasks. Extraocular photoreceptors include deep brain photoreceptors located in several distinct brain sites and the pineal complex, involving intracranial (pineal and parapineal) and extracranial (frontal organ and parietal eye) components. This review updates the research field of the most recent acquisitions concerning the roles of extraocular photoreceptors on circadian physiology and behavior, particularly photic entrainment and sun compass orientation.     

Molecular mechanisms of entrainment in the Neurospora circadian clock

Light and temperature are 2 of the most important environmental influences on all circadian clocks, and Neurospora provides an excellent system for understanding their effects. Progress made in the past decade has led to a basic molecular understanding of how the Neurospora clock works and how environmental factors influence it. The purpose of this review is to summarize what we currently know about the molecular mechanism of light and temperature entrainment in Neurospora.     

The effects of chronic marijuana use on circadian entrainment

Animal literature suggests a connection between marijuana use and altered circadian rhythms. However, the effect has not yet been demonstrated in humans. The present study examined the effect of chronic marijuana use on human circadian function. Participants consisted of current users who reported smoking marijuana daily for at least a year and non-marijuana user controls. Participants took a neurocognitive assessment, wore actigraphs and maintained sleep diaries for three weeks. While no significant cognitive changes were found between groups, data revealed that chronic marijuana use may act as an additional zeitgeber and lead to increased entrainment in human users.     

A newt's eye view of lens regeneration

In this paper we describe the basic process of lens regeneration in adult newt and we pinpoint several issues in order to obtain a comprehensive understanding of this ability, which is restricted to only a few salamanders. The process is characterized by dynamic changes in the organization of the extracellular matrix in the eye, re-entering of the cell cycle and dedifferentiation of the dorsal iris pigment epithelial cells. The ability of the dorsal iris to contribute to lens regeneration is discussed in light of iris-specific gene expression as well as in relation to factors present in the eye.     

Season- and latitude-dependent effects of simulated twilights on circadian entrainment

Groups of Syrian hamsters were exposed to LD cycles with twilight transitions and photoperiods simulating natural lighting conditions at the summer solstice (SS), equinox, and winter solstice (WS) at 41 degrees N and at the winter solstice at the Arctic Circle (WS 66 degrees N) but with daytime illuminance truncated at 10 lux (LD-twilight). Separate groups were kept under matching rectangular cycles (LD-rectangular). The inclusion of twilights affected several circadian parameters in a season-and latitude-dependent manner. The most striking difference was in the timing of activity onsets, which followed dusk in the presence of twilights but were more closely related to dawn (lights-on) in their absence. Activity offsets and midpoints were also earlier in LD-twilight than in LD-rectangular, with the differences being most pronounced under WS 66 degrees N. In LD-twilight, longer nights resulted in earlier offsets and midpoints, but in LD-rectangular, midpoints were later under long than under short nights while offsets did not vary significantly. In LD-twilight, activity duration (alpha) increased monotonically with increasing nighttime duration, but in LD-rectangular, alpha was shorter under WS 66 degrees N than under WS conditions. These effects of season and latitude observed in LD-twilight were similar to those reported in animals exposed to natural illumination, while those observed in LD-rectangular differed in several respects. The presence of twilights also resulted in lower day-to-day variability in activity onset times (greater precision), supporting the earlier conclusion that twilights increase the strength of the LD zeitgeber. Free-running periods in constant darkness (DD) were shorter in LD-twilight than in LD-rectangular, especially under WS 66 degrees N, raising the possibility that the effects of twilights on the timing of the entrained activity rhythm reflect their effects on the period of that rhythm. Increasing daytime illuminance to 100 lux (WS conditions only) resulted in earlier activity offsets and midpoints and a shorter alpha but had no effect on activity onsets or on subsequent period in DD. These results indicate that exposure to low twilight illuminances alone can account for several of the documented differences between the effects of natural and rectangular light cycles on circadian entrainment.     

The role of Clock in the plasticity of circadian entrainment

The mammalian circadian clock lying in suprachiasmatic nucleus (SCN) is synchronized to about 24 h by the environmental light-dark cycle (LD). The circadian clock exhibits limits of entrainment above and below 24 h, beyond which it will not entrain. Little is known about the mechanisms regulating the limits of entrainment. In this study, we show that wild-type mice entrain to only an LD 24 h cycle, whereas Clock mutant mice can entrain to an LD 24, 28, and 32 h except for LD 20 h and LD 36 h cycle. Under an LD 28 h cycle, Clock mutant mice showed a clear rhythm in Per2 mRNA expression in the SCN and behavior. Light response was also increased. This is the first report to show that the Clock mutation makes it possible to adapt the circadian oscillator to a long period cycle and indicates that the clock gene may have an important role for the limits of entrainment of the SCN to LD cycle.     

Neural induction. A bird's eye view

Since the discovery of the phenomenon of neural induction by Spemann and Mangold in 1924, considerable effort has been invested in identifying the signals produced by the organizer that are responsible for diverting the fate of cells from epidermal to neural. Substantial progress has been made only recently by the finding in amphibians that BMP4 is a neural inhibitor and epidermal inducer, and that endogenous antagonists of BMPs are secreted by the organizer. However, recent results in the chick point to the existence of other, upstream events required before BMP inhibition stabilizes neural fates. Here we take a critical view of the evidence for and against the view that BMP inhibition is a sufficient trigger for neural induction in different vertebrates.