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

Elife. 2019 Mar 26;8:e43996. doi: 10.7554/eLife.43996.

Abstract

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.

Keywords: Hippo; LATS; SOX2; YAP; mouse; pituitary stem cell; pituitary tumour; regenerative medicine; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation*
  • Gene Deletion
  • Gene Regulatory Networks
  • Mice
  • Pituitary Gland / cytology*
  • Pituitary Gland / embryology
  • Pituitary Gland / growth & development
  • Protein-Serine-Threonine Kinases / metabolism*
  • SOXB1 Transcription Factors / analysis
  • Signal Transduction*
  • Stem Cells / chemistry
  • Stem Cells / physiology*
  • Trans-Activators / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Trans-Activators
  • Tumor Suppressor Proteins
  • Wwtr1 protein, mouse
  • Yap protein, mouse
  • Lats1 protein, mouse
  • LATS2 protein, mouse
  • Protein-Serine-Threonine Kinases