The evolution and development of cell number and organ size

Cells are the building blocks of all multicellular organisms and changes in cell number have important consequences for organismal form, function and evolution. Evolutionary changes in cell number can alter the appearance and physiology of individual organs and body plans, and therefore contribute to organismal diversity. Incorrect specification of cell number results in the development of organs that are too large or too small, and uncontrolled expansion of cell number results in cancer.

Therefore, understanding the regulation of cell number is vital to expanding our knowledge about the specification of organ size and function, the evolution of the shape and size of plants and animals, and the genetic and developmental bases of diseases including cancer. It follows that it is essential to fully describe the developmental mechanisms and genetic factors that regulate cell number especially in the case of the specification of organ size about which little is known.

Screening for new genes and studying the function of known genes and pathways that affect cell number has provided many insights into the regulation of cell number. However, studying natural variation in cell number provides a powerful approach that compliments these other strategies. This is because organisms that exhibit natural variation in cell number and organ size must contain and express the genetic and developmental changes that cause these changes. Therefore, identifying the genetic and developmental bases of natural variation in cell number between organisms will not only reveal how these changes have evolved but provides new insights into how these processes are regulated.

In this proposal we will describe the changes in development that cause natural differences in cell number that cause the eyes of Drosophila to be larger or smaller by up to 5000 cells in each eye. We will also map the genetic variants underling these changes in cell number and investigate how these changes alter the genetic regulation of eye size. As well as revealing the developmental and genetic bases of evolutionary differences in cell number, this will provide new insights into the specification of cell number, and this data will be used to generate predictive models to understand the regulation of cell number and organ size in animals more broadly.

The regulation of cell number is crucial for the evolution and development of multicellular organisms. Cell number evolution can lead to adaptive changes to organ size and function. Mis-regulation of cell number can cause development of tumours or incorrectly sized organs that do not function properly. Therefore, it is vital to fully characterise the developmental genetic regulation of cell number to understand the specification and evolution of organ size and function, of which little is currently known, as well as providing new insights into the causes of many diseases including cancer.

Genetic screens and functional characterisation of known genes and signaling pathways has provided many insights into cell number regulation. However, studying natural variation in cell number is a powerful complimentary strategy because organisms that exhibit natural variation in cell number and organ size clearly contain and express the developmental genetic changes that cause this variation. Therefore, identifying the developmental genetic basis of cell number differences between populations and/or closely related species will not only reveal how these changes have evolved but provides new insights into the cell number regulation.

We propose to identify the changes in development that cause natural variation in eye size of up to 250 ommatidia between sexes and strains of D. melanogaster and D. simulans. To do this we will quantify cell division and morphogenetic furrow progression to determine if similar changes in one or both of these processes underlie ommatidia number differences between sexes and species. We will also map the genetic basis of intra-specific variation and investigate how these variants alter the genetic regulation of eye size. As well as revealing the developmental genetic basis of cell number evolution, this research will provide new insights into cell number specification, and facilitate predictive modeling of cell number and organ size regulation.

This proposal will have a beneficial impact on individuals and organisations in both private and public sectors through three main mechanisms. First, via collaboration and staff training. Second, given the importance of cell number and differentiation in human development and disease, we envision potential long-term social and economic benefits of this work. Third, through engagement with the children, teachers and members of the public about the aims and importance of our research and basic science generally.

Collaboration and Training
The new collaboration in this proposal between Oxford Brookes University (OBU) and the Centro Andaluz de Biologia del Desarrollo in Seville, Spain, will catalyse further exchange of knowledge and people in the future benefitting the two countries, institutions and the individuals involved. Moreover, scientific progress is often driven by multidisciplinary approaches and consequently there is great demand for scientists with training in different fields and who can approach problems from different perspectives. This multidisciplinary philosophy and skills development is accounted for in this proposal because we will collaborate with experts in developmental biology and computational biology. In addition to providing this broad scientific training, the RCI and technician will have access to a specific training program at OBU and will receive training in transferable skills including oral and written presentations, mentoring, computing, and management. Public sector areas from primary to higher education and private sector research could potentially benefit from the staff training and skills development in this project as a result. The benefits of this training and support for the RCI will ultimately result in a researcher with transferable skills trained for a career in research, teaching or internationally competitive in other employment sectors. In addition, the technician will be trained in state-of-the-art techniques in developmental genetics and molecular biology, which will greatly enhance her/his contribution to high quality research in academia or industry in the future. Academia and society generally will also benefit from this proposal because it will promote the career of a talented and well-trained female RCI, and thus will contribute to widening opportunities for women in science.

Social and Economic Impact
While our proposal is a basic science project, changes in regulation of cell number and differentiation play a major role in the development and evolution of all plants and animals, including humans, and are involved in cancer and human eye disorders when perturbed. Therefore, our proposal has the potential to provide better understanding of human disease, and could eventually even lead to the commercial development of drugs for their treatment. Therefore the results of our study will benefit those in the medical and pharmaceutical sectors, and thus eventually patients with eye conditions.

Engagement
This proposal represents an excellent opportunity to engage children, teachers and the public in how basic research impacts on more applied areas of research such as human biology and medicine. Thus widening their interest in genetics and development, and importantly, how this can impact circumstances in everyday life. Therefore, by engaging the public in the objectives and results of this project through our outreach activities, this proposal has the potential to inform and interest children and teachers about basic science, and improve communication between scientists and the public generally to the benefit of both. The general public will benefit from improved science education and clearer understanding of the objectives of basic science, which is likely to benefit charities that fund research from public donations. Science will benefit from a greater public understanding of basic research because this will positively influence funding and policy.