Targeted disruption of the pituitary glycoprotein hormone alpha-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 a-subunit and unique ~-subunit, and heterodimerization is required for function. No mutations in the a-subunit or any of the 13-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 a-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 13-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.

Engineering physiologically regulated insulin secretion in non-β cells by expressing glucagon-like peptide 1 receptor

“…In the pituitary of an adult male rat, the most abundant cell types are somatotrophs and lactotrophs (constituting 50 and 15%, respectively, of the anterior pituitary cells). 29,30 The hormone release profiles presented in Figure 2a are consistent with these data, showing that GH and PRL secretion levels were the highest found in the perifusate. Insulin released by the transduced cells in response to TRH far exceeded the small, but consistent, amounts released in response to the other releasing factors.…”

“…29,30 Corticotrophs secrete adrenocorticotropin (ACTH) after stimulation with corticotropin-releasing hormone (CRH); growth hormonereleasing hormone (GHRH) acts on somatotrophs and releases growth hormone (GH); gonadotrophs secrete luteinizing hormone/follicle-stimulating hormone (LH/ FSH) when they are stimulated by gonadotropin-releasing hormone (GnRH); both thyrotrophs and lactotrophs respond to thyrotropin-releasing hormone (TRH) and secrete TSH and prolactin (PRL), respectively. It was demonstrated previously that recombinant adenovirus could mediate gene transfer into each of these endocrine cell populations.…”

Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4

“…Mice with growth retardation often display defects in pituitary structure or function, which may become apparent as an ultimate defect in GH or thyroid-stimulating hormone (TSH) production or secretion (25)(26)(27)29). Despite the lack of structural abnormalities of the pituitaries of TR4 Ϫ/Ϫ mice, it is possible that TR4 affects pituitary hormone-initiated signaling at points further downstream.…”

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5

“…Although neither TSH nor the TSHR are required for the initial formation of the thyroid gland during development (42), the lack of signaling through the TSHR leads to thyroid hypoplasia in mature animals (1,(43)(44)(45), and overstimulation of cAMP production in the thyroid either artificially (46)(47)(48) or by stimulation of the TSHR (49, 50) leads to thyroid hyperplasia. However, we found the thyroid glands of OGH-TG mice to be grossly normal in weight and appearance.…”