BIOLOGY OF THE CONGENITALLY HYPOTHYROID HYT HYT MOUSE/

The hyt/hyt mouse has an autosomal recessive, fetal onset, characteriz ed by severe hypothyroidism that persists throughout life and is a rel iable model of human sporadic congenital hypothyroidism. The hypothyro idism in the hyt/hyt mouse reflects the hyporesponsiveness of the thyr oid gland to thyrotropin (TSH). This is attributable to a point mutati on of C to T at nucleotide position 1666, resulting in the replacement of a Pro with Leu at position 556 in transmembrane domain IV of the G protein-linked TSH receptor. This mutation leads to a reduction in al l cAMP-regulated events, including thyroid hormone synthesis. The dimi nution in T-3/T-4 in serum and other organs, including the brain, also leads to alterations in the level and timing of expression of critica l brain molecules, i.e. selected tubulin isoforms (M beta 5, M beta 2, and M alpha 1), microtubule associated proteins (MAPs), and myelin ba sic protein, as well as to changes in important neuronal cytoskeletal events, i.e. microtubule assembly and SCa and SCb axonal transport. In the hyt/hyt mouse, fetal hypothyroidism leads to reductions in M beta 5, M beta 2, and M alpha 1 mRNAs, important tubulin isoforms, and M b eta 5 and M beta 2 proteins, which comprise the microtubules. These mo lecules are localized to layer V pyramidal neurons in the sensorimotor cortex, a site of differentiating neurons, as well as a site for loca lization of specific thyroid hormone receptors. These molecular abnorm alities in specific cells and at specific times of development or matu ration may contribute to the observed neuroanatomical abnormalities, i .e. altered neuronal process growth and maintenance, synaptogenesis, a nd myelination, in hypothyroid brain. Abnormal neuroanatomical develop ment in selected brain regions may be the factor underlying the abnorm alities in reflexive, locomotor, and adaptive behavior seen in the hyt /hyt mouse and other hypothyroid animals. (C) 1997 Elsevier Science Lt d.