Developmental requirements and network properties of the Drosophila circadian clock circuit

Abstract

CLOCK/CYCLE (CLK/CYC) and PERIOD/TIMELESS (PER/TIM) are heterodimers which cyclically inhibit one another transcriptionally and post-translationally, required in adult Drosophila for the molecular oscillation controlling daily rhythms in activity. Prior work in the lab established that developmental reduction of PER and subsequent adult reintroduction does not affect adult rhythmic behaviour, whilst developmental PER overexpression or CYC reduction does. I sought to characterise the developmental role of CYC. Developmental CYC reduction specific to metamorphosis can impact adult behavioural rhythms, but CYC restriction throughout development does not appear to disrupt adult molecular rhythms. Developmental CYC restriction results aberrant neuroanatomy of small lateral ventral neurons (s-LNv), which control freerunning rhythmicity, with increased complexity and defects indicative of defective axonal function, which are present in late larval and early pupal stages. Spatial mapping reveals loss of CYC in neurons other than the s-LNvs contributes to this defect. However, the adult behavioural phenotype of a developmental CYC deficit is also associated with apparent defects in other clock neurons and expression markers for other clock-gene-expressing neurons indicate that developmental specification of these cells is altered in the absence of CYC. CYC mutants display a nocturnal profile in light-dark cycles, which cannot be rescued by adult-specific CYC. Nocturnality is a circuit property independent of s-LNvs, or the neuropeptide that bolsters s-LNv function, pigment-dispersing factor (PDF), which can be overriden by developmental CYC expression within s-LNvs.

I characterised a network state, driven by continued photic stimulation via the visual pathway, histamine signalling and large lateral ventral neurons (l-LNvs) which, in the absence of activation of a blue-light photoreceptor, CRY, encoded by the cryptochrome gene, which allows autonomous light sensitivity in clock-gene-expressing cells, results in a hierarchical shift in which s-LNvs, and the neuropeptide through which they interact with other clock neurons, PDF, are dispensible for behavioural rhythms. Behaviour is not rescued in this network state following developmental CYC loss, echoing additional defects beyond the PDF cells, though developmental CYC rescue in PDF-negative clock cells can restore rhythmicity in this condition.

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ORCID for Herman Wijnen: orcid.org/0000-0002-8710-5176

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