Principles of the animal molecular clock learned from Neurospora

Abstract

Study of Neurospora, a model system evolutionarily related to animals and sharing a circadian system having nearly identical regulatory architecture to that of animals, has advanced our understanding of all circadian rhythms. Work on the molecular bases of the Oscillator began in Neurospora before any clock genes were cloned and provided the second example of a clock gene, frq, as well as the first direct experimental proof that the core of the Oscillator was built around a transcriptional translational negative feedback loop (TTFL). Proof that FRQ was a clock component provided the basis for understanding how light resets the clock, and this in turn provided the generally accepted understanding for how light resets all animal and fungal clocks. Experiments probing the mechanism of light resetting led to the first identification of a heterodimeric transcriptional activator as the positive element in a circadian feedback loop, and to the general description of the fungal/animal clock as a single step TTFL. The common means through which DNA damage impacts the Oscillator in fungi and animals was first described in Neurospora. Lastly, the systematic study of Output was pioneered in Neurospora, providing the vocabulary and conceptual framework for understanding how Output works in all cells. This model system has contributed to the current appreciation of the role of Intrinsic Disorder in clock proteins and to the documentation of the essential roles of protein post‐translational modification, as distinct from turnover, in building a circadian clock.

Phosphorylation Hypothesis of Sleep

“…In addition, PER/FRQ and their responsible kinase CKI, as well as other binding partners, form a macromolecular complex ( Aryal et al, 2017 ; Liu et al, 2019 ), the status of which (e.g., binding affinity of each component) may be changed slowly by multisite phosphorylation within the complex. In a sense, the slow dynamics produced by the collective and cooperative interaction of protein complexes driven by multisite phosphorylation may act as a timer to count the length of a 24-h period in eukaryotes ( Larrondo et al, 2015 ; Dunlap and Loros, 2018 ; Ode and Ueda, 2018 ; Diernfellner and Brunner, 2020 ; Loros, 2020 ; Partch, 2020 ).…”

Microbes in the Era of Circadian Medicine

“…Among fungi, the ascomycete Neurospora crassa is the only model system in which the presence of a well-defined molecular clock has been systematically studied and documented. Along with Drosophila melanogaster, N. crassa has represented a model organism for the study of the circadian rhythms and has been instrumental to decipher the molecular mechanisms underlying its functioning (Loros, 2019). The current model of the circadian rhythm in N. crassa identifies in the White Collar Complex (WCC), a heterodimer formed by the two transcription factors White Collar 1 (WC-1) and White Collar 2 (WC-2), the basis for the Transcriptional Translational Feedback Loop (TTFL) (Larrondo and Canessa, 2019).…”

Circadian rhythmicity and the community of clockworkers

“…It is generally accepted that circadian rhythms with fundamentally identical characteristics occur in all eukaryotes, with the caveat that relatively few organisms have been studied. In this issue, we have insights from three simple model systems, namely the cyanobacteria, a prokaryote (Golden, ), and eukaryotic organisms, yeast and Neurospora (Causton, ; Loros, ). The prokaryote Synechococcus elongatus circadian clock is the simplest known to date.…”

“…These properties enable the biochemical examination of metabolic oscillatory mechanisms (Causton, ). Work on Neurospora (Loros, ) takes advantage of the operating similarities among organisms underlying circadian clocks. In a simplified version, clocks are based upon a feedback loop, in which two proteins constitute a heterodimeric switch that drives expression of one or more genes.…”