Award details

Specification of forebrain territories: commitments and signalling.

Reference	BB/E005403/1
Principal Investigator / Supervisor	Professor Corinne Houart
Co-Investigators / Co-Supervisors
Institution	King's College London
Department	MRC Ctre for Developmental Neurobiology
Funding type	Research
Value (£)	413,450
Status	Completed
Type	Research Grant
Start date	08/08/2006
End date	07/02/2010
Duration	42 months

Abstract

The general organisation of the forebrain is largely conserved in vertebrates. The forebrain comprises the dorso-rostrally positioned telencephalon and eyes, the ventrally positioned hypothalamus the dorso-posteriorly located epithalamus (including the pineal gland and habenula), the prethalamus and the thalamus (both sitting between hypothalamus and epithalamus) and finally the caudal most pretectum. Forming between the prethalamus and thalamus is a prominent boundary region termed the zona limitans intrathalamica (zli), a structure that may constitute a separate subdivision of the diencephalon Fate-mapping studies, although incomplete in all model species, have helped to reveal the neural plate origins of the cells that comprise the different regions of the forebrain. Telencephalic precursors are located rostral and lateral to the eye field, adjacent to the anterior margin of the neural plate Diencephalic precursor cells are located caudal to the eye field. We have very recently completed both an expression and a fate map of the presumptive diencephalon at bud stage (late gastrulation). Our findings suggest an early regionalisation of the area into at least 5 sub-domains. As we had previously found that some cells inside the diencephalic anlage were specified and irreplaceable, we are setting out to define how many diencephalic cell populations are committed to a restricted fate during late gastrulation. By collaboration with Prof. Lumsden in our Centre, we will also draw expression profiles of transcripts specific to each diencephalic domain. We then aim to address the function of some of these transcripts, specifically located inside presumptive pre-thalamic or thalamic neural plate area. Finally, we will test whether any of these domains have the properties of a signalling centre.

Summary

In all vertebrates, from fish to humans, the brain is formed of three main regions, the forebrain, midbrain and hindbrain. The forebrain gives rise to our cortex, in which our conscious thoughts, emotions and many of our memories reside. It also forms the eyes and the diencephalon. How the forebrain region becomes sub-divided into telencephalon (future cortex), eye and diencephalon remains a mystery. Our aim is to understand the mechanisms underlying this subdivision. A significant number of early brain malformations observed in human foetuses (for instance following viral infection in early stage of pregnancy, or more rarely indeed by genetic defects) are due to mistakes in the steps required for normal forebrain partition. Knowing the mechanisms required for normal forebrain development will therefore help understanding the cause of these human malformations. The brain comes from a simple sheet of tissue, called neural plate. This plate closes into a tube from which the most rostral end develops into the forebrain. We already discovered that some of the decisions required to divide the forebrain into specific areas are taken before the formation of the neural tube, inside the rostral neural plate. We showed that the anterior neural border (the most rostral end of the neural plate, ANB) is required for formation of the telencephalon and is a source of signalling that needs to be received by the rostral plate in order for these cells to become telencephalon and subsequently form a cortex. We also gathered preliminary results suggesting that other irreversible decisions are taken in the neural plate. These decisions are establishing the precursors for specialised areas of the diencephalon. In this proposal, we aim to identify the neural plate cell populations that are the earliest to commit to a defined diencephalic identity and to test whether these cells are sending signals potentially able to orchestrate the identities of the areas surrounding them. We will alsoget a profile of the different genes that are specifically expressed in each of the studied neural plate areas, in order to get insight into the molecular nature of their differences. By the end of the three years of research, we will have identified the earliest commitments leading to specific diencephalic areas and anticipate identifying some of the molecular players underlying the establishment of the diencephalic subdivisions. We also hope to identify a novel signalling centre responsible for some of the early organisation of the forebrain territory.

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Neuroscience and Behaviour, Stem Cells
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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