Control of Cell-Cell interactions in Forebrain Morphogenesis.

In human, between 2 and 3% of babies are born with birth defects; half of these suffering of mild to severe brain and/or eye impairments. In 40% of these, brain defect is accompanied by changes in brain and/or eye size. Understanding the source of these severe brain and eye conditions in new-born is a pre-requisite to plan therapeutic avenues.
We found that mistakes in the very early separation between telencephalon (forming the future brain hemispheres) and eye, leads to abnormalities in brain and eye size in the animal model used in our lab (the zebrafish). This finding open the possibility that some of the pathologies related to microcephaly (smaller brain) or macrocephaly (bigger brain) may originate from early segregation defects.
We very recently identified four key players in the process of separation between telencephalon and eye but have very little knowledge of how they act and how they connect to each other.
In this proposal our goals are to:
- Understand the exact nature of events required for correct separation of telencephalon and eye in fish and mouse.
- Characterize the extent of brain and eye abnormalities induced by impaired brain/eye separation
- Identify the conserved molecular interactions that are orchestrating the separation process.

In completion of this programme of research, we will have identified the conserved cellular events driving normal formation of telencephalon and eye in vertebrates and established a model of functional molecular network controlling this process. We will also have linked our finding to human genetics and associated genes of the network to specific human brain malformations, strengthening the potential relation between tissue segregation defect and human developmental brain disorders.

Tissue segregation and boundary formation is essential to normal brain development. This has been particularly well-studied in the context of hindbrain development, while our understanding of forebrain regionalisation is still very partial. The very first and crucial forebrain tissue segregation takes place at the onset of neural plate closure. In order to initiate vesicle formation, the precursors of the eye adopt a very different behaviour than their telencephalic and diencephalic neighbours. Differential cellular behaviour and normal forebrain morphogenesis rely on coordinated cell movement inside each defined cell populations as well as formation of a well defined boundary between the eye field and the rest of the forebrain. The last 10 years saw the elucidation of the key molecular events required to establish the different forebrain areas (telencephalon, eye field and diencephalon) in vertebrates. However, although we understand the patterning mechanisms that give neural plate territories their identity, we don't have any knowledge of what forms and maintains segregation and boundaries between forebrain territories during neurulation. This proposal aims to fill this important knowledge gap and identify the molecular and cellular events underpinning segregation of telencephalon and eye territories during neurulation. The knowledge of the molecular interactions involved will not only further our comprehension of forebrain development but will also shed light upon molecular interplay between effectors of tissue segregation and allow us to explore the possible implication of early segregation defects in mammalian micro/macrocephaly.

1. Academic impact
The expected beneficiaries of this research proposal are mainly the scientists in the fields of cell biology, developmental neurobiology and neuro-developmental disorders.
2. From basic research to clinic
Likely beneficiaries are clinicians working on neurodevelopmental disorders as this project will also lead to identification of novel molecules and molecular mechanisms that will have impact on the understanding of birth defects therefore impacting on human health. We will engage with clinicians both by participating to clinical symposia and by extending our interactions and collaborations with these clinicians.
The lead applicant already have funded collaboration with clinicians at the Institute of Psychiatry and is a co-lead of the Wellcome Trust consortium Deciphering Mechanisms of Developmental Disorders (DMDD).
Dynamic communication and exchange of results will ensure the identification of results directly relevant to human health and will facilitate the design of translational follow-on research projects.
3. Application and exploitation:
Any commercial potential of our discoveries will be discussed with KCL enterprise. However, no obvious commercial outcome is predicted from this proposal.
4. Communications and engagement:
The lead applicant is communicating her results through public lectures in school and public events organised by various organisations. She also teaches at and direct international courses and organises international workshops (eg. EMBO. MBL).
The lead applicant is in the process of developing a Centre website for the public.

The findings will be shared with the public. All peer-reviewed articles will be published in Open Access format and findings will be explained in the form of public lectures and illustrations/3D model made for public science exhibitions.