Endocrine Abstracts (2009) 20 S28.4

Thyroid hormone signaling during brain development: genetic dissection in mouse

Frédéric Flamant

ENS Lyon, Lyon, France.

Thyroid hormone (T3) has been known for a long time to be required for brain development which activate TRα and TRβ nuclear receptors. In rodent models, histological defects are mainly observed in cerebellum. Whether T3 action during cerebellum development is due to direct regulation of gene transcription by liganded thyroid hormone receptors (mainly TRα) or also the indirect consequences of other defects and systemic disorders is currently unknown.

In order to unravel the direct and indirect effect of T3 during mouse cerebellum development we have used the CRE/loxP recombination technology to express a mutant form of the TRα1 isoform able to block T3 signaling in a controlled manner.

Whereas ubiquitous expression of this mutation recapitulates most if not all features of congenital hypothyroidism in the post-natal mouse cerebellum, restricted expression indicate that in some neuronal cell types, the action is cell autonomous whereas in other, indirect effects, perhaps mediated by neurotrophic factors or cell contacts, are involved.

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