Understanding biomineralisation in the fish dermal skeleton and its role in health and development

By 2020 global fish production had already exceeded 179 million tonnes, and is thought to contribute £600 million to the British economy. In addition to this, zebrafish are the second most highly used species in biomedical research, after mouse. Therefore, understanding mechanisms relating to health and wellbeing of fish is vital.

Much of fish development echoes that of humans and mammals in many ways. For example, the requirement for a mineralised skeleton to provide organ protection, mobility, and calcium-phosphorous homeostasis. However, unlike mammals, fish often possess a second mineralised skeleton, by way of their scales.

In addition to the roles listed above, this dermal skeleton provides protection from the hostile external environment from injury and infection. Skeletal mineralisation has been shown to be detrimentally impacted in rapidly grown animals of agricultural importance, such as pigs and chickens, as well as several human disorders. In the race to produce more sustainable, cheaper protein, research into how these farming methods might affect calcium maintenance in these fish (via scale mineralisation), and how that may impact on their health and wellbeing is sorely lacking.

We know that these scales mineralise in a similar way to bones, but for both bones and scales, we don't fully understand how the underlying processes lead to mineralisation.

Mineralisation begins with an extracellular collagen rich matrix, which confers toughness to the tissue and acts as a scaffold on which the mineral component, hydroxyapatite (calcium - phosphate complex) is embedded, conferring stiffness to the composite material. How hydroxyapatite is initially formed has been widely debated for many years, but it is now considered to centre upon the concentration of calcium and phosphate within matrix vesicles which are themselves released by bone and scale cells.

Matrix vesicles are small (100-300nm) vesicles, which contain a number of proteins responsible for the accumulation of calcium and phosphate. It has not been possible to ascertain how matrix vesicles are released from the cell. I hypothesise that matrix vesicles are released from the surface of the cell, following cytoskeletal rearrangement as identified in a number of cell membrane-based processes.

I propose developing a scheme of work that will allow me to understand the importance of mineralisation in fish health and wellbeing, as well as having broader implications for the understanding of mineralisation at the molecular level, across species. In this fellowship, I will develop robust imaging techniques to image matrix vesicles. Using live cell imaging, I will manipulate proteins of interest, to elucidate their role in vesicle biogenesis and trafficking of proteins.

I will further develop these imaging techniques to study matrix vesicle biogenesis in fish scales. Furthermore, I will use fish lines with a range of mineralisation phenotypes to study the importance of scale mineralisation in wound healing for fish and develop preliminary research into the extent of mineralisation changes in aquaculture species bred for meat.

These studies will offer opportunities for high impact publications within this fellowship, as well as forming the basis for future senior fellowships, grant applications and studentships.