Pituitary gland development and disease: from stem cell to hormone production

Abstract

Many aspects of pituitary development have become better understood in the past two decades. The signaling pathways regulating pituitary growth and shape have emerged, and the balancing interactions between the pathways are now appreciated. Markers for multipotent progenitor cells are being identified, and signature transcription factors have been discovered for most hormone-producing cell types. We now realize that pulsatile hormone secretion involves a 3D integration of cellular networks. About a dozen genes are known to cause pituitary hypoplasia when mutated due to their essential roles in pituitary development. Similarly, a few genes are known that predispose to familial endocrine neoplasia, and several genes mutated in sporadic pituitary adenomas are documented. In the next decade, we anticipate gleaning a deeper appreciation of these processes at the molecular level, insight into the development of the hypophyseal portal blood system, and evolution of better therapeutics for congenital and acquired hormone deficiencies and for common craniopharyngiomas and pituitary adenomas.

Keywords: Adenohypophysis; Anterior pituitary; Neural ectoderm; Organizing center; Rathke’s pouch; Stem cell.

Fig. 1. Signaling pathways initiating in the organizing center regulate anterior pituitary gland growth and shape

The oral ectoderm invaginates at the roof of the mouth to produce Rathke’s pouch (black). The overlying neural ectoderm is defined molecularly by expression domain of Shh and Six6 and a more dorsal region expressing Bmp and Fgf. These regions exert inhibitory effects on each other, creating a balance that induces normal patterning and growth of Rathke’s pouch. The interaction between stimulatory and inhibitory transcription factors and signaling molecules is diagrammed (right).

Fig. 2. Regulation of the cell cycle

Immunostaining for phospho-histone H3 (PHH3) and incorporation of bromodeoxyuridine (BrdU) marks the mitosis (M) and synthesis (S) phases of the cell cycle. Ki67 staining is absent in quiescent cells. Association of E2F with Rb is disrupted when Rb is phosphorylated at the juncture between G1 and S phase. A variety of cyclins and cyclin dependent kinases are expressed and have critical roles at specific points in the cell cycle.