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The shortwave-sensitive class I of visual pigments in vertebrates has the widest variation in peak sensibility, ranging from ultraviolet (355-390 nm) to violet (390-440 nm). Phylogenetic evidence indicates that the ancestral pigment was probably UV-sensitive (UVS) and that the shifts between violet and UV have occurred several times throughout vertebrate evolution. These appear to be two major tuning mechanisms present in vertebrates: one in the non-avian vertebrates and one in the avian group. Avian UVS pigments have Cys90 while VS pigments have Ser90. Non-avian UVS pigments have Phe86, which is replaced in VS pigments. The objective of this project has been to extend our understanding of the molecular basis of SWS1 pigment tuning by addressing whether the effect of the residues present at these sites are consistent across different vertebrate orders. Within the mammalian order, it has been possible to elucidate the SWS1 tuning mechanism within the rodent lineage, showing that the VS pigment in the grey squirrel has a different tuning mechanism compared to the guinea pig and that nocturnal flying squirrels have dispensed with colour vision. The visual system of the platypus, a montreme from the bases of the mammalian radiation has also been investigated and shown to have retained colour vision by a different route from all other mammals. An analysis of the tuning mechanism of primate VS pigments has shown that violet-sensitivity was achieved though a unique mechanism. In the avian order the results have shown that the ancestral avian pigment became VS through a Ser86 substitution and only later did extant bird species utilize site 90 to re-create UV sensitivity. The presence of UVS pigments has also been investigated in long-lived parrot species; partial sequences have revealed that all species possess Cys90, indicating the presence of a UVS pigment in fifteen species of parrots.

Dietary restriction (DR), the reduction in food intake that falls short of starvation, has been shown to be the most robust and reproducible intervention to extend lifespan in diverse organisms ranging from yeast to mammals, including the fruit fly Drosophila. Despite over 70 years of research, primarily on rodents, the mechanisms by which DR extend lifespan in any organism are poorly understood, partially due to the variation in how DR is defined and applied between laboratories. Lifespan extension by DR commonly trade-offs with reduced fecundity, leading to evolutionary-based theories predicting that DR elicits an evolved response to food shortage in nature, through reallocation of resources away from reproduction and towards somatic maintenance, hence increasing the chance of survival until food supply becomes more abundant. In Drosophila, DR is typically implemented by dilution of sucrose and yeast in an agar-based medium, with yeast being the key component regulating lifespan. Firstly, this thesis presents an investigation of the response of the model organism Drosophila to different DR diets and protocols, thereby creating one standardized and optimized DR diet for use. Secondly, using the optimized diet, this project investigates the role of specific nutrients mediating the effects of DR and the potential pathways controlling these effects. Essential amino acids were shown to directly regulate the trade-off between high fecundity and reduced lifespan observed with full feeding. However, methionine addition alone was necessary and sufficient to increase fecundity to levels seen with full feeding, without reducing lifespan, demonstrating that reallocation of nutrients cannot explain the DR responses. The results of this thesis highlight the importance for a standard DR protocol and suggest that in other organisms, including mammals, the beneficial effects of DR may be achieved without impairing fertility by using a suitable balance of nutrients in the diet.

Left-right asymmetry is a highly conserved feature of the nervous system. However, it is not known how functional lateralisation is represented at the level of lateral differences in circuit microarchitecture. In this study, I identify asymmetric neuronal connectivity in the larval zebrafish brain, resolve L-R differences in the morphology and connectivity of individual projection neurons and investigate the molecular and cellular mechanisms by which lateralisation develops. The habenular nuclei form part of the highly conserved dorsal dien cephalic conduction system. I find that the habenulae display laterotopic ef ferent connectivity, wherein left and right-sided axons are segregated along the dorso-ventral axis of their target, the interpeduncular nucleus (IPN). Habenular neurons elaborate remarkable "spiralling" terminal arbors within the IPN. I have identified two sub-types of habenular neuron, defined by ax onal arbors with distinct morphology and targeting. Both sub-types are found in both the left and right habenula, but in substantially different ratios. Thus, the vast majority of left habenular neurons elaborate tall, crown-shaped arbors localised to the dorsal IPN, whereas almost all right- sided cells form flattened arbors restricted to the ventral IPN. This left- right asymmetry in cell-type composition, combined with the differential targeting of neuronal sub-types, underlies the laterotopic connectivity of the habenulae. This reveals a fundamental strategy that serves to differentiate functional circuitry on the two sides of the CNS: equivalent components are specified on both sides and lateralisation results from differences in the ratios of neuronal sub-types on the left and right. Left-sided Nodal signalling is essential for controlling the orientation, or laterality, of laterotopic connectivity, but is not required for asymmetry per se. The left-sided parapineal nucleus is required for the development of normal asymmetric phenotypes, including the development of both left and right-sided axon arbors with appropriate morphology and targeting. How ever, following laser-ablation of the parapineal, left and right-sided neurons continue to elaborate arbors with distinct lateralised morphologies, indicating that additional developmental mechanisms act to convey left-right identity information to this highly conserved circuit.

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No description available.