Journal Article

Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade

Santambrogio, Alice, Johnson, Randy L, Thavaraj, Selvam, Russell, John P, Jacques, Thomas S, Xekouki, Paraskevi, Andoniadou, Cynthia Lilian, Lodge, Emily J, Bornstein, Stefan R

2019

Overview

SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis. The pituitary is a gland inside the head that releases hormones that control major processes in the body including growth, fertility and stress. Diseases of the pituitary gland can prevent the body from producing the appropriate amounts of hormones, and also include tumours. A population of stem cells in the pituitary known as SOX2 cells divide to make the specialist cells that produce the hormones. This population forms as the pituitary develops in the embryo and continues to contribute new hormone-producing cells throughout life. Signals from inside and outside the gland control how the pituitary develops and maintain the correct balance of different types of cells in the gland in adults. In 2016, Lodge et al. reported that a cascade of signals known as the Hippo pathway is active in mouse and human pituitary glands, but its role remained unclear. Here, Lodge et al. use genetic approaches to study this signalling pathway in the pituitary of mice. The results of the experiments show that the Hippo pathway is essential for the pituitary gland to develop normally in mouse embryos. Furthermore, in adult mice the Hippo pathway is required to maintain the population of SOX2 cells in the pituitary and to regulate their cell numbers. Increasing the level of Hippo signalling in mouse embryos and adult mice led to an expansion of SOX2 stem cells that could generate new specialist cell types, but a further increase generated aggressive tumours that originated from the uncontrolled growth of SOX2 cells. These findings are the first step to understanding how the Hippo pathway works in the pituitary, which may eventually lead to new treatments for tumours and other diseases that affect this gland. The next step towards such treatments will be to carry out further experiments that use drugs to control this pathway and alter the fate of pituitary cells in mice and other animals.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adaptor Proteins, Signal Transducing - metabolism / Animals / Brain cancer / Brain tumors / Cancer / Carcinogenesis / Cell Cycle Proteins - metabolism / Cell Proliferation / Clonal deletion / Dentistry / Embryo / Gene Deletion / Gene Regulatory Networks / Genetic research / Genotype & phenotype / Hippo / Homeostasis / Hormones / Kinases / LATS / Mice / Observations / Phosphorylation / Physiological aspects / Physiology / Pituitary / Pituitary gland / Pituitary Gland - cytology / Pituitary Gland - embryology / Pituitary Gland - growth & development / pituitary stem cell / pituitary tumour / Protein Serine-Threonine Kinases - metabolism / Proteins / Signal Transduction / SOX2 / SOXB1 Transcription Factors - analysis / Stem cells / Stem Cells - chemistry / Stem Cells - physiology / Stem Cells and Regenerative Medicine / Trans-Activators - metabolism / Transcription factors / Tumor Suppressor Proteins - metabolism / Tumorigenesis / Tumors / YAP / YAP-Signaling Proteins / Yes-associated protein