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Michael Brunner 
Circadian Rhythms and Molecular Clocks

Groupleader: Michael Brunner

Current Research

The Molecular Clock of Neurospora crassa

Most organisms have evolved circadian clocks to anticipate environmental changes associated with the 24h night-day cycle of earth rotation. Circadian clocks modulate rhythmic expression of a large number of genes (~10% in eukaryotic organisms) and thus generate the potential to control thousands of biochemical, physiological and behavioral functions in a time-of-day specific manner. Circadian clocks are cell-autonomous oscillators. They are composed of a network of interconnected positive and negative feedback loops that produce rhythmic expression and modification of one or more clock proteins. Circadian oscillations are self-sustained and persist without environmental cues with a ca. 24 h period. In nature, environmental signals, so-called �zeitgebers�, are transduced to the circadian clock to synchronize the clock with the 24 h period of earth rotation. The strongest zeitgebers are light, temperature and nutrients.
Using the filamentous fungus Neurospora crassa as a model organism, we aim to understand how the circadian clock works as a program that coordinates complex expression profiles in a temporal fashion.
The frequency (frq) gene is a key element of the circadian clock of Neurospora. Expression levels of frq RNA and FRQ protein oscillate in a circadian fashion. Expression of frq is controlled by the transcription factors White Collar-1 (WC-1) and WC-2. These GATA-type zink-finger transcription factors assemble into a hetero-oligomeric complex, the White Collar Complex (WCC). They bind to two specific elements in the frq promoter and activate clock-controlled frq RNA transcription as well as transcription of frq in response to light. FRQ protein is a dimeric phosphoprotein which is part of a negative feedback loop inhibiting synthesis of its own RNA. In the course of a day FRQ protein is progressively hyperphosphorylated and degraded. As the levels of FRQ protein decrease the negative feedback is gradually relieved. frq RNA levels begin to rise and a new circadian period starts. However, FRQ does not only act as a repressor of its own RNA. It also supports accumulation of WC-1 and WC-2. The positive feedback of FRQ on WC �1 accumulation appears to be due to a post-transcriptional function of FRQ, while the positive effect of FRQ on WC-2 expression is on the level of transcription.

Future Projects and Goals

The assembly of clock protein complexes, the translocation of these complexes into the nucleus and the regulated degradation of clock protein complexes are key steps in timekeeping on the molecular level. The mechanisms underlying the positive and negative feedback loops of the molecular clock and the temporal and spatial coordination of the various clock protein interactions are in the main focus of our research. The FRQ/WCC oscillator modulates rhythmic expression of about 1000 Neurospora genes. Only a fraction of these genes are directly controlled by WCC. The organization and regulation of the network of clock-controlled genes is a further focus of the lab.

Interactions of the circadian clock protein FREQUENCY (FRQ) with the clock transcription factors
                                        WHITE COLLAR-1 and -2 (WC-1 and WC-2).

Download BZH Report Brunner 2011-2013