No abstract

The anterior pituitary gland is comprised of specialized cell-types that produce and secrete polypeptide hormones in response to hypothalamic input and feedback from target organs. These specialized cells arise during embryonic development, from stem cells that express SOX2 and the pituitary transcription factor PROP1, which is necessary to establish the stem cell pool and promote an epithelial to mesenchymal-like transition, releasing progenitors from the niche. Human and mouse embryonic stem cells can differentiate into all major hormone-producing cell types of the anterior lobe in a highly plastic and dynamic manner. More recently human induced pluripotent stem cells (iPSCs) emerged as a viable alternative due to their plasticity and high proliferative capacity. This mini-review gives an overview of the major advances that have been achieved to develop protocols to generate pituitary hormone-producing cell types from stem cells and how these mechanisms are regulated. We also discuss their application in pituitary diseases, such as pituitary hormone deficiencies.

Pituitary hormone deficiency occurs in ~1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated hypopituitarism patients that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant negative loss of function. Using a high throughput splicing reporter assay, we tested 1,080 single nucleotide variants in POU1F1. We identified 113 splice disruptive variants, including 23 synonymous variants. We evaluated separate cohorts of hypopituitarism patients and found two different synonymous splice disruptive variants that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in the POU1F1 gene.