The specification and development of choroid plexus

Brain and spinal cord comprise a single system organised around a fluid filled tube. Within the brain, this tube expands into a series of larger chambers, each lined with a specialised, blood vessel enriched tissue called the choroid plexus. This plexus acts as a barrier between the blood system and brain, protecting nerve cells from infection. It also makes the cerebrospinal fluid, which fills the neural tube. Problems in the development of this system of chambers, named ventricles, and their choroid plexus are associated with a variety of developmental disorders in humans from hydrocephalus to schizophrenia. Despite its significance, many fundamental questions about the development of the choroid plexus remain unanswered. How is its formation coordinated with both neural development and the blood supply growing in from the body? Why do ventricles and choroid plexus form in the brain but not the spinal cord? We believe that the answers to first of these questions lie at the junction between the choroid plexus and the brain. Here, the secreted molecules that play a role in organising how nerve cells grow may also signal to the developing blood vessels and tissues of the plexus. We believe that clues as to why only some brain regions make choroid plexus lie in events that occur at and just after the neural tube forms. Patterns and pathways of cell mixing at the edges of the tube as they knit together appear point to fundamental differences between brain and spinal cord. Our proposal will address these questions in simple animal model systems where cell movements, gene function and blood vessel growth can be visualised and manipulated using cutting edge experimental approaches. The results of our experiments will contribute to the fundamental knowledge of brain development that underlies advances in neurology.

Problems in the development of the choroid plexus are associated with a variety of developmental disorders in humans from hydrocephalus to schizophrenia. This plexus acts as a barrier between the blood system and brain, protecting nerve cells from infection. It also produces cerebrospinal fluid, which mediates the supply of nutrients and morphogens to developing neurons. Despite its significance, many fundamental questions about the development of the choroid plexus remain unanswered. In particular, how does the brain choreograph the development of the choroid plexus epithelium and its associated blood supply? Why do ventricles form in the brain but not the spinal cord? In preliminary experiments we have established that the boundary between neural tube and future choroid epithelium is a signalling centre. We have performed a microarray screen to determine new signalling molecules and markers of primitive choroidal epithelium. Additionally, we have established that the specification of choroidal roofplate epithelium may be prefigured by differences in the way that neural folds knit together during neural tube closure. These observations form the basis of this proposal to examine the principles of choroid plexus development. Using microsurgical, gene overexpression, cell labelling and time-lapse microscopy approaches in chick and zebrafish we will examine three specific hypotheses: 1) Boundary-organiser cells at the margin of the roofplate organise choroidal epithelium specification and blood vessel formation. 2) Establishment of this organiser depends on patterns of asymmetric planar dispersal of the derivatives of a boundary stem cell division. 3) Competence to make choroid plexus is predetermined by cell and lineage mixing at the dorsal midline very early in development.

Beyond academic beneficiaries our research has made a significant and demonstrable contribution to the third sector (museums and galleries) in both UK and internationally and to the general public through public engagement activity. This proposal will continue in this record of success in both stimulating public interest and support for empirical research. The questions that we address in this proposal are fundamental questions about the origins of the brain and its functions. These have an enduring interest outside academia and a potential and capacity to stimulate where other fields do not. Our continuing engagement with museums and galleries will ensure that beneficiaries will share in the rapid dissemination of the ideas, images and communication of science data. The general success of such activity can be measured in high attendance rates at initiatives such as the Wellcome Collection and the Darwin Centre at the Natural History Museum. The continued high level of public interest in science is testament to how much science collaborations within this sector can achieve. Specific beneficiaries of our research in the third sector include have included the Science Museum (London), Design Museum (Zurich), Rotterdam Film Festival (Netherlands) in addition to BBC radio and television. Current activities involve a dissemination of research perspectives through an exhibition planned for the Deutsches Hygiene-Museum (Dresden) and the Moravian Gallery (Brno) in 2011.