Developmental Regulation and Pathogenesis of Pituitary Corticotroph Function

Abstract

The different cell lineages of the pituitary gland arise sequentially during organogenesis, which, in the mouse, takes place between days 10 and 18 (e10–e18) of fetal development. The corticotroph lineage is the first to appear with the first POMC‐positive cells being detected at e12.5. Differentiation of this lineage has now been linked to a number of organ‐ or cell‐restricted transcription factors. In corticotrophs, the homeobox transcription factor Pitx1 (Ptx1), the bHLH factor BETA2/NeuroD1, and the Tbox factor Tpit all play essential roles for cell‐specific transcription of the POMC gene and for development. Pitx1, together with Pitx2, marks the embryological origin of the pituitary in the anterior surface ectoderm and it is an important regulator in all pituitary lineages. Importantly, Pitx1 is required for protein:protein interactions with cell‐restricted factors, such as NeuroD1 and Tpit. NeuroD1 is transiently‐expressed in fetal corticotrophs where it is important for POMC expression. Tpit is a highly cell‐restricted transcription factor since it is only present in mouse corticotrophs and melanotrophs. Tpit is important for terminal differentiation of corticotrophs, but it is not required for commitment to this lineage. Tpit‐deficient mice present with an isolated deficiency of pituitary ACTH (IAD), which results in adrenal insufficiency and hypoplasia. This phenotype is extremely similar to a neonatal onset form of IAD that we defined in the course of a search for human TPIT gene mutations. So far, at least 13 different mutations have been found in the human TPIT gene within more than 20 different families of various ethnic origins. These patients define a very homogenous clinical presentation of neonatal IAD. It is possible that this entity was not previously recognized because of the neonatal lethality associated with it.