PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells

Abstract

Mutations in PROP1 are the most common cause of hypopituitarism in humans; therefore, unraveling its mechanism of action is highly relevant from a therapeutic perspective. Our current understanding of the role of PROP1 in the pituitary gland is limited to the repression and activation of the pituitary transcription factor genes Hesx1 and Pou1f1, respectively. To elucidate the comprehensive PROP1-dependent gene regulatory network, we conducted genome-wide analysis of PROP1 DNA binding and effects on gene expression in mutant mice, mouse isolated stem cells and engineered mouse cell lines. We determined that PROP1 is essential for stimulating stem cells to undergo an epithelial to mesenchymal transition-like process necessary for cell migration and differentiation. Genomic profiling reveals that PROP1 binds to genes expressed in epithelial cells like Claudin 23, and to EMT inducer genes like Zeb2, Notch2 and Gli2. Zeb2 activation appears to be a key step in the EMT process. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation.DOI: http://dx.doi.org/10.7554/eLife.14470.001

Regulation of pituitary stem cells by epithelial to mesenchymal transition events and signaling pathways

“…In support of this idea, we discovered that Prop1 is transiently co-expressed with Sox2 in embryonic pituitary development, and using Prop1 mutant mice we showed that Prop1 is required for initial establishment of adequate stem cell pools, as well as for normal stem cell colony forming behavior (11). Prop1 mutant neonates have more SOX2-positive cells than wild-types, and they remain in the marginal zone (Figure 4).…”

“…This tissue is thought to be the stem cell niche and is referred to as the marginal zone. There is an EMT-like transition, including a reduction in E-cadherin expression at the ventral aspect of the Rathke’s cleft, as anterior lobe progenitor cells begin to differentiate and delaminate ventrally and migrate laterally from the lumen, causing the expansion of the parenchyma of the anterior lobe (11,31,32). …”

“…Gene expression profiling of adherent stem cell colonies revealed that many genes in the Notch, TGFβ, WNT and SHH signaling pathways were down-regulated in Prop1 mutants. In addition, Prop1 mutant colonies have up-regulated epithelial cell markers like E-cadherin, keratins and claudins, and down-regulation of mesenchymal cell markers like metalloproteinases and the EMT inducer Zeb2 (11). Studies in intact animals confirmed that Prop1 is required for activation of genes like Zeb2 and Slug (32,95).…”

“…In vitro differentiation of both human and mouse embryonic stem (ES) cells into pituitary hormone producing cells in culture has been successfully developed and improved upon in recent years, shedding light on mechanisms which could stimulate differentiation of pituitary stem cells in vivo (7–10). The composition of the stem cell niche is being investigated, and an epithelial to mesenchymal (EMT-like process was shown to drive migration of progenitors out of the niche (11). Pathways regulating cell turnover are being identified (12), and the limitations of self-renewal over the life of the animal are emerging (13).…”

Basic Research Advances on Pituitary Stem Cell Function and Regulation

“…The localisation of PROP1 marks a proportion of SOX2+ cells that are able to form colonies in vitro, but this was shown to be required for enabling transition to the progenitor state and for leaving the epithelium via epithelial-mesenchymal transition [32]. SOX9+ cells (also expressing SOX2) do generate functional cells of all lineages in vivo [21], but the difference in potential between single SOX2+ only and double SOX2;SOX9 is not yet known, neither is the functional requirement for SOX9.…”