Targeted disruption of the pituitary glycoprotein hormone α-subunit produces hypogonadal and hypothyroid mice

Abstract

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 α-subunit and unique β-subunit, and heterodimerization is required for function. No mutations in the α-subunit or any of the β-subunit genes have been reported in mice. To assess directly the functional role of TSH, LH, and FSH in thyroid and gonadal development, we created a disruption of the α-subunit gene by homologous recombination. The homozygous mutant animals were hypogonadal and exhibited profound hypothyroidism resulting in dwarfism. Thyroid development was arrested in late gestation, but GnRH neuron migration, development of secondary sex organs, and fetal and neonatal gonadal development were normal. This establishes the importance of thyrotropin in ontogeny and reveals that fetal pituitary gonadotropins are not required for sexual differentiation or genital development in male or female fetuses. The pituitary cells that produce TSH β-subunit exhibited dramatic hypertrophy and hyperplasia as a result of the lack of thyroid function. This proliferative response occurred at the expense of somatotrope and lactotrope cells, consistent with a derivation of these three cell types from a common precursor.