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.
Highlights
Hereditary pituitary hormone deficiency, or hypopituitarism, is the most common pituitary disease in children and can cause significant morbidity if not treated effectively (Vimpani et al, 1977)
Genetic tracing experiments revealed that Sox2-expressing cells in the embryonic pituitary give rise to Sox2-expressing cells postnatally and to all the hormone-producing cell types of the anterior pituitary gland, demonstrating that SOX2-positive cells are the pituitary stem cells (Rizzoti et al, 2013; Andoniadou et al, 2013)
We recently demonstrated that all the hormone-producing cells of the anterior and intermediate lobes of the pituitary gland pass through a Prop1 expressing intermediate (Davis et al, 2016)
Summary
Hereditary pituitary hormone deficiency, or hypopituitarism, is the most common pituitary disease in children and can cause significant morbidity if not treated effectively (Vimpani et al, 1977). Normal pituitary gland development involves invagination of oral ectoderm to create Rathke’s pouch and evagination of the overlying neural ectoderm, which contains the FGF and BMP signaling center that stimulates pituitary growth. The stem cells in Rathke’s pouch express SOX2, and as they transition to differentiation, they delaminate from the ventral aspect of the cleft, migrate ventrally and rostrally, and become the glandular parenchyma of the anterior lobe (Ward et al, 2005; Rizzoti et al, 2013; Garcia-Lavandeira et al, 2009). Notch signaling is required to prevent premature differentiation (Zhu et al, 2006; Raetzman et al, 2004), but the molecular mechanisms for stimulating progenitors to migrate and differentiate are unknown; and these processes are of central importance for understanding pituitary organogenesis and the pathophysiology of congenital pituitary hormone deficiency
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