Endocrine Abstracts

The pituitary is an anatomically well protected endocrine gland in permanent contact with the central nervous system. Although it was known that pituitary has plasticity in response to the physiological demands of the body, there were few clear data about the post-natal mechanisms in charge of this plasticity. The discovery of a group of cells expressing stem cell markers precisely organized in the outer zone of the adenopituitary open up new possibilities to explain the constant pituitary renewal. Moreover, the organization and location of these cells is conserved from rodents (mouse and rat) to human pituitary suggesting an essential role of this structure called the GPS niche. The GPS cells express the tyrosine-kinase receptor RET together with two of its co-receptors GFRa2 and GFRa3 (G). But also they retain expression of PROP1 (P) a key transcription factor during pituitary embryonic development, while they co-express markers of pluripotency such as SOX2, OCT4 and KLF4 (S). Opposite GPS cells do not express any pituitary hormone or transcription factors associated to differentiation as for example Pit-1. The data obtained so far indicate that more than one type of cells can exist around the GPS. The precise characterization of markers together with functional studies suggest a true niche of stem cells. The GPS niche could be implicated in disease as data obtained in human cranyopharingiomas suggest.

But if new cells are being recruited from the niche to the adenopituitary to replace those which are old or non-functional, we should explain how unfit cells are isolated and marked for removal. Our recent data in rodent somatotrophs indicate that the RET receptor, when is not activated by the ligand through another co-receptor GFRa1, is intracellularly processed by Caspase 3 triggering a mechanism of arrest and cell death. Thus, RET over-activates the Pit-1 promoter, Pit-1 excess directly activates the ARF promoter increasing ARF expression which in turn stabilizes p53 leading to cell death. New data in somatotroph adenoma cultures indicate that the pathway is conserved in humans.

In summary, the data gathered at present highlight the importance of GPS cells in pituitary cell renewal and further our understanding on the mechanisms leading to pituitary hyperplasia, pituitary adenomas, and related tumors such as craniopharyngiomas.