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

View Article: PubMed Central - PubMed

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

No MeSH data available.


Related in: MedlinePlus

Model of Prop1’s role in the transition of stem cells to differentiation.During normal pituitary development when stem cells transition toward differentiation they exit the cell cycle and express Cyclin E. Our results suggest that for progenitors to differentiate they need to go through an EMT-like process where E-cadherin is down-regulated and the cells lose adhesion. In the absence of Prop1, the expression of genes that can induce EMT, like Zeb2, is reduced, leading to increased cell adhesion and increased expression of tight junction proteins like claudins. Our data suggest that PROP1 is required for progenitors to progress to the transitional stage marked by Cyclin E expression embryonically, and in the absence of Prop1, Sox2 expression is elevated. The failure of progenitors cells to advance to the transitional stage leads to pituitary hormone deficiency and organ dysmorphology.DOI:http://dx.doi.org/10.7554/eLife.14470.017
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fig10: Model of Prop1’s role in the transition of stem cells to differentiation.During normal pituitary development when stem cells transition toward differentiation they exit the cell cycle and express Cyclin E. Our results suggest that for progenitors to differentiate they need to go through an EMT-like process where E-cadherin is down-regulated and the cells lose adhesion. In the absence of Prop1, the expression of genes that can induce EMT, like Zeb2, is reduced, leading to increased cell adhesion and increased expression of tight junction proteins like claudins. Our data suggest that PROP1 is required for progenitors to progress to the transitional stage marked by Cyclin E expression embryonically, and in the absence of Prop1, Sox2 expression is elevated. The failure of progenitors cells to advance to the transitional stage leads to pituitary hormone deficiency and organ dysmorphology.DOI:http://dx.doi.org/10.7554/eLife.14470.017

Mentions: In summary, we showed that Prop1 is required for normal stem cell pools during embryogenesis and postnatal pituitary expansion. Our genome-wide analyses support the idea that Prop1 promotes the transition of progenitors to differentiation by inducing expression of EMT drivers like Zeb2. In addition, Prop1 activates expression of cyclin E, a marker of the transition state, and Pou1f1, a marker of the differentiation state (Figure 10). This study establishes the mechanism of PROP1 action in pituitary progenitor cells, offers new candidate genes for cases of pituitary hormone deficiency with unknown etiology, and lays the foundation for investigating the role of EMT in pituitary tumor formation.10.7554/eLife.14470.017Figure 10.Model of Prop1’s role in the transition of stem cells to differentiation.


PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells
Model of Prop1’s role in the transition of stem cells to differentiation.During normal pituitary development when stem cells transition toward differentiation they exit the cell cycle and express Cyclin E. Our results suggest that for progenitors to differentiate they need to go through an EMT-like process where E-cadherin is down-regulated and the cells lose adhesion. In the absence of Prop1, the expression of genes that can induce EMT, like Zeb2, is reduced, leading to increased cell adhesion and increased expression of tight junction proteins like claudins. Our data suggest that PROP1 is required for progenitors to progress to the transitional stage marked by Cyclin E expression embryonically, and in the absence of Prop1, Sox2 expression is elevated. The failure of progenitors cells to advance to the transitional stage leads to pituitary hormone deficiency and organ dysmorphology.DOI:http://dx.doi.org/10.7554/eLife.14470.017
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4940164&req=5

fig10: Model of Prop1’s role in the transition of stem cells to differentiation.During normal pituitary development when stem cells transition toward differentiation they exit the cell cycle and express Cyclin E. Our results suggest that for progenitors to differentiate they need to go through an EMT-like process where E-cadherin is down-regulated and the cells lose adhesion. In the absence of Prop1, the expression of genes that can induce EMT, like Zeb2, is reduced, leading to increased cell adhesion and increased expression of tight junction proteins like claudins. Our data suggest that PROP1 is required for progenitors to progress to the transitional stage marked by Cyclin E expression embryonically, and in the absence of Prop1, Sox2 expression is elevated. The failure of progenitors cells to advance to the transitional stage leads to pituitary hormone deficiency and organ dysmorphology.DOI:http://dx.doi.org/10.7554/eLife.14470.017
Mentions: In summary, we showed that Prop1 is required for normal stem cell pools during embryogenesis and postnatal pituitary expansion. Our genome-wide analyses support the idea that Prop1 promotes the transition of progenitors to differentiation by inducing expression of EMT drivers like Zeb2. In addition, Prop1 activates expression of cyclin E, a marker of the transition state, and Pou1f1, a marker of the differentiation state (Figure 10). This study establishes the mechanism of PROP1 action in pituitary progenitor cells, offers new candidate genes for cases of pituitary hormone deficiency with unknown etiology, and lays the foundation for investigating the role of EMT in pituitary tumor formation.10.7554/eLife.14470.017Figure 10.Model of Prop1’s role in the transition of stem cells to differentiation.

View Article: PubMed Central - PubMed

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

No MeSH data available.


Related in: MedlinePlus