Delayed detyrosination of alpha-tubulin from parallel fibre axons and its correlation with impaired synaptogenesis in hypothyroid rat cerebellum.

The biochemical basis of retarded differentiation and maturation of microtubules and impaired synaptogenesis in hypothyroidism has been investigated by studying the temporal and spatial relationship between alpha-tubulin detyrosination in the parallel fibre axons of rat cerebellum and alterations in the activity of the detyrosinating enzyme, TTCP (tubulinyl tyrosine carboxypeptidase) with the progress of synaptogenesis in the molecular layer. Detyrosination was monitored by following the disappearance of stain from cerebellar sections, immunocytochemically labeled with a monoclonal antibody (20C6) specific for alpha-tubulin, tyrosinated at the C-terminal end. With respect to normal controls, detyrosination of alpha-tubulin from the parallel fibres of the molecular layer during synaptogenesis was not only delayed by about 5 days but also prolonged in the hypothyroid cerebellum. Correspondingly, the increase of TTCP activity in the developing thyroid deficient cerebellum was also delayed by about 1 week. Comparison of the developmental profile of TTCP activity in the normal and hypothyroid cerebellum during synaptogenesis revealed that the overall activity of the enzyme in the thyroid deficient cerebellum was reduced to almost half of that of the normal controls. These results establish that thyroid hormones are essential for the induction of TTCP, which catalyses detyrosination during the normal ontogenic development of rat cerebellum. Since our data also suggest that detyrosination precedes synaptic contacts to generate a class of differentiated microtubules functionally competent for synaptogenesis, the delayed detyrosination in the hypothyroid cerebellum may desynchronize the normal developmental program resulting in incomplete synaptogenesis.