Laranjeiro, RFF; (2014) Circadian clock regulation of the zebrafish cell cycle and developmental gene expression. Doctoral thesis , UCL (University College London).

Abstract

The circadian clock is known to regulate a wide range of physiological and cellular processes, yet remarkably little is known about its role during embryo development. Zebrafish offer a unique opportunity to explore this issue, not only because a great deal is known about key developmental events, but also because of the highly decentralised nature of its circadian system. Moreover, specific stages of the cell cycle are clock-controlled in zebrafish cell lines and during embryo development, making zebrafish an ideal model to explore the interactions between these two cellular oscillators. This thesis presents: i. Identification of an evolutionarily conserved cell cycle regulator, cyclin-dependent kinase (CDK) inhibitor 1d or p20, which is closely related to the CDK inhibitor p21. Both p20 and p21 are rhythmically expressed, directly clock-controlled, and regulators of the G1/S transition of the cell cycle. However, their expression patterns differ both temporally and spatially, leading to a unique mechanism whereby S-phase is set to different times of the day in a tissue-specific manner, depending on the balance of these two inhibitors. ii. Description of a wide range of day lengths to which the zebrafish circadian clock can be entrained (from at least 16 to 32 hr days). Clock entrainability is demonstrated by rhythmicity of both clock-related gene expression and cell cycle timing. Furthermore, this remarkable wide range of entrainment for a vertebrate is observed both in vitro (zebrafish cell lines) and in vivo (zebrafish larvae). iii. Identification of numerous rhythmic genes during zebrafish development, including neuroD and additional transcription factors whose rhythmic expression is restricted to the developing retina. Rather surprisingly, however, these circadian expression rhythms are only observed in differentiated retinal photoreceptors (both in larvae and adults), suggesting a new and important role in regulating the rhythmic expression of phototransduction components.

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