Principles of the animal molecular clock learned from Neurospora

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. Neurospora crassa, a genetically tractable model system, has informed the study of animal clocks. Within the oscillator core is a heterodimeric PAS‐domain transcription factor that activates expression of proteins that enter a negative element complex capable of blocking positive element activity. The heterodimer also activates clock‐controlled genes, leading to rhythmic cascades of gene expression within the cell. Light resets clock phase by changing the amount of the negative element complex.