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 alpha-subunit and unique beta-subunit, and heterodimerization is required for function. No mutations in the alpha-subunit or any of the beta-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 alpha-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 beta-subunit exhibited dramatic hypertrophy and hyperplasia as a result of the lack of thyroid function. This proliferation response occurred at the expense of somatotrope and lactotrope cells, consistent with a derivation of these three cell types from a common precursor.
Kendall
S K
SK
Cell and Molecular Biology Program, University of Michigan Medical School, Ann Arbor 48109-0618, USA.
Samuelson
L C
LC
Saunders
T L
TL
Wood
R I
RI
Camper
S A
SA
D000375:Aging / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D001755:Blastocyst / Q000502:physiology; D002478:Cells, Cultured; D002678:Chimera; D003001:Cloning, Molecular; D017931:DNA Primers; D004392:Dwarfism / Q000235:genetics*; D004622:Embryo, Mammalian; D005260:Female; D005640:Follicle Stimulating Hormone / Q000096:biosynthesis*; D015292:Glycoprotein Hormones, alpha Subunit / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D006965:Hyperplasia; D006984:Hypertrophy; D007006:Hypogonadism / Q000235:genetics*; D007037:Hypothyroidism / Q000235:genetics*; D007986:Luteinizing Hormone / Q000096:biosynthesis*; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010902:Pituitary Gland / Q000473:pathology; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis; D012733:Sex Differentiation; D013234:Stem Cells; D013972:Thyrotropin / Q000096:biosynthesis*; D014162:Transfection
D017931:DNA Primers; D015292:Glycoprotein Hormones, alpha Subunit; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013972:Thyrotropin