Sk. Kendall et al., TARGETED DISRUPTION OF THE PITUITARY GLYCOPROTEIN HORMONE ALPHA-SUBUNIT PRODUCES HYPOGONADAL AND HYPOTHYROID MICE, Genes & development, 9(16), 1995, pp. 2007-2019
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.