Pitx2 and Pitx1 regulate thyrotroph function and response to hypothyroidism

Abstract

Pitx2 is a home domain transcription factor required in a dose-dependent manner for the development of multiple organs. Pitx2-null homozygotes (Pitx2 -/-) have severe pituitary hypoplasia, whereas mice with reduced-function alleles (Pitx2 neo/neo) exhibit modest hypoplasia and reduction in the developing gonadotroph and Pou1f1 lineages. PITX2 is expressed broadly in Rathke's pouch and the fetal pituitary gland. It predominates in adult thyrotrophs and gonadotrophs, although it is not necessary for gonadotroph function. To test the role of PITX2 in thyrotroph function, we developed thyrotroph-specific cre transgenic mice, Tg(Tshb-cre) with a recom-bineered Tshb bacterial artificial chromosomethat ablatesfloxed genes in differentiated pituitary thyrotrophs. We used the best Tg(Tshb-Cre) strain to generate thyrotroph-specific Pitx2-deficient offspring, Pitx2 flox/-;Tg(Tshb-cre). Double immunohistochemistry confirmed Pitx2 deletion. Pitx2 flox/-;Tg(Tshb-cre) mice have a modest weight decrease. The thyroid glands are smaller, although circulating T 4 and TSH levels are in the normal range. The pituitary levels of Pitx1 transcripts are significantly increased, suggesting a compensatory mechanism. Hypothyroidism induced by low-iodine diet and oral propylthiouracil revealed a blunted TSH response in Pitx2 flox/-; Tg(Tshb-cre) mice. Pitx1 transcripts increased significantly in control mice with induced hypothyroidism, but they remained unchanged in Pitx2 flox/-;Tg(Tshb-cre) mice, possibly because Pitx1 levels were already maximally elevated in untreated mutants. These results suggest that PITX2 and PITX1 have overlapping roles in thyrotroph function and response to hypothyroidism. The novel cre transgene that we report will be useful for studying the function of other genes in thyrotrophs. © 2011 by The Endocrine Society.