Research objectives and content This project is concerned with the early stages of mammalian central nervous system differentiation and patterning. Conventionally, it is thought that a derivative of the primitive streak, the early mesendoderm, induces the overlying ectoderm to differentiate into rostral CNS: midbrain and forebrain. However recent results from Dr Beddington's laboratory indicate that the first inductive signal may arise from primitive endoderm (which does not contribute to the fetus itself) rather than from mesendoderm. Several genes expressed in the anterior primitive endoderm at the time of induction have now been isolated and mutations in many of them cause varying degrees of holoprosencephaly or more severe anterior truncations. I plan to investigate the role of the primitive endoderm in inducing anterior central nervous system using three approaches. Firstly, using tissue recombination experiments in vitro, I plan to test the ability of the anterior primitive endoderm to ectopically induce anterior neural structures. Secondly, using transient transgenesis experiments employing a primitive endoderm specific promoter, I plan to ectopically express candidate genes (which from their expression profile or mutant phenotype are implicated in normal anterior CNS patterning) and to evaluate whether they can anteriorise embryonic development during gastrulation. Finally, attempts will be made to 'expression-clone' mouse cDNAs encoding anterior CNS inducers using Xenopous as the developmental assay.
Training content (objective, benefit and expected impact) These approaches would confirm that the initial signal defining the anterior aspect of the embryo emanates from primitive endoderm and may lead to the isolation of some of the molecular components of such an interaction.
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