Positive and negative regulations by FGF8 contribute to midbrain roof plate developmental plasticity

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Abstract
The roof plate (RP) of the midbrain shows an unusual plasticity, as it is duplicated or interrupted by experimental manipulations involving the mid/hindbrain organizer or FGF8. In previous experiments, we have found that FGF8 induces a local patterning center, the isthmic node, that is essential for the local development of a RP. Here, we show that the plasticity of the midbrain RP derives from two apparently antagonistic influences of FGF8. On the one hand, FGF8 widens beyond the neural folds the competence of the neuroepithelium to develop a RP by inducing the expression of LMX1B and WNT1. Ectopic overexpression of these two factors is sufficient to induce widely the expression of markers of the mature RP in the midbrain. On the other hand, FGF8 exerts a major destabilizing influence on RP maturation by controlling signaling by members of the TGFβ superfamily belonging to the BMP, GDF and activin subgroups. We show in particular that FGF8 tightly modulates follistatin expression, thus progressively restraining the inhibitory influence of activin B on RP differentiation. These regulations, together with FGF8 triggered apoptosis, allow the formation of a RP progress zone at some distance from the FGF8 source. Posterior elongation of the RP is permitted when the source of FGF8 withdraws. Growth of the posterior midbrain neuroepithelium and convergent extension movements induced by FGF8 both contribute to increase the distance between the source of FGF8 and the maturing RP. Normally, the antagonistic regulatory interactions spread smoothly across the midbrain. Plasticity of midbrain RP differentiation probably results from an experimentally induced imbalance between regulatory pathways.