Pituitary development and disease: from stem cells to the Pou1f1 lineage

CHEUNG L; PÉREZ MILLÁN M I; CAMPER SA; BRINKMEIER ML; MORTENSEN AH

Conferencia; FASEB Conference: Growth Hormone/Prolactin Family in Biology & Disease; 2017

FASEB Conference: Growth Hormone/Prolactin Family in Biology & DiseaseSteamboat Springs, ColoradoJuly 23-28, 2017Pituitary development and disease: from stem cells to the Pou1f1 lineage1Camper SA, 1Cheung LYM, 1Mortensen AH, 1Brinkmeier ML, 2Pérez Millán MI1Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA2 Institute of Biomedical Research, UBA-CONICET, Buenos Aires, C121ABG ArgentinaHuman growth insufficiency occurs about 1/4000 children. Isolated Growth Hormone Deficiency (IGHD) is the most common pituitary malfunction in childhood, and combined pituitary hormone deficiency (CPHD) is the second. IGHD progresses to CPHD in about 45% of the cases. Worldwide, only 16% of CPHD cases can be explained by mutations in known genes, and mutations in the pituitary specific transcription factor PROP1 are the most common cause. About 11% of IGHD is explained genetically, and the known causes include mutations in the GH gene or the receptors that regulate GH secretion. Prop1 is the first pituitary specific gene in the hierarchy of transcription factors that regulate pituitary development. Genes required to activate PROP1 and PROP1 targets, like POU1F1, are also mutated in cases of CPHD. To better understand the mechanism of PROP1 action, we identified the genome-wide set of PROP1 target genes and PROP1-dependent changes in gene expression. These studies reveal that PROP1 regulates the transition of pituitary stem cells to hormone producing cells in an epithelial to mesenchymal-like transition process, which is a component of organogenesis and the transition to invasive cancer in many other organ systems. PROP1 is necessary to maintain progenitor proliferation, migration, and pituitary placode fate identity. It is also necessary for retinoic acid and BMP signaling. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation and shed light on the mechanism whereby it activates the POU1F1 lineage.