TARGETED DISRUPTION OF THE PITUITARY GLYCOPROTEIN HORMONE ALPHA-SUBUNIT PRODUCES HYPOGONADAL AND HYPOTHYROID MICE

Pituitary thyrotropin (TSH) and gonadotropins (LH and FSH) are thought to be critical for thyroid and gonadal development and function. Each of these pituitary hormones is a heterodimer composed of a common alp ha-subunit and unique beta-subunit, and heterodimerization is required for function. No mutations in the alpha-subunit or any of the beta-su bunit genes have been reported in mice. To assess directly the functio nal role of TSH, LH, and FSH in thyroid and gonadal development, we cr eated a disruption of the alpha-subunit gene by homologous recombinati on. The homozygous mutant animals were hypogonadal and exhibited profo und hypothyroidism resulting in dwarfism. Thyroid development was arre sted in late gestation, but GnRH neuron migration, development of seco ndary sex organs, and fetal and neonatal gonadal development were norm al. This establishes the importance of thyrotropin in ontogeny and rev eals that fetal pituitary gonadotropins are not required for sexual di fferentiation or genital development in male or female fetuses. The pi tuitary cells that produce TSH beta-subunit exhibited dramatic hypertr ophy and hyperplasia as a result of the lack of thyroid function. This proliferative response occurred at the expense of somatotrope and lac totrope cells, consistent with a derivation of these three cell types from a common precursor.