The anterior pituitary functions as the endocrine core of the organism, regulating hormonal synthesis and secretion to effect adaption to changing metabolic and reproductive needs. Deficiencies of pituitary-derived hormones, due to genetic causes, head injury, under or over-nutrition, or as a consequence of pituitary cancer treatment cause severe morbidity. The cells of the anterior pituitary have been long known to possess remarkable plasticity of fate suggesting the presence of stem cell-like cell populations. However, whether stem cells do indeed contribute to cell plasticity and pituitary recovery and the underlying mechanisms that control pituitary cell plasticity in response to pituitary injury, changing hormonal demands or tumor progression have not been established. The mRNA translation control protein, Musashi, has been shown to plays a critical role in mediating physiological and pathological stem cell function in many tissue types. Musashi mediates stem cell self renewal by repressing translation of target mRNAs that encode proteins required for cell cycle inhibition and cell differentiation. Our data indicate that Musashi is broadly expressed in the adult anterior pituitary in non-stem cell populations, as well as in pituitary stem cells. The overall objective of this application is to assess the role of regulated mRNA translation in general, and the Musashi protein specifically, in mediating adaptive changes of cell fate in the pituitary. The central hypothesis is that Musashi controls both pituitary stem/progenitor cell differentiation and also plasticity of hormone producing cells in the adult pituitary. Specifically, studies for Aim 1 will use both in vivo mouse models and cell culture approaches to test the hypothesis that Musashi regulates cell plasticity during tissue regeneration as well as developmental pituitary stem/progenitor cell function. Studies for Aim 2 will use unbiased polysome-based, RNA-sequencing approaches to test the hypothesis that Musashi has gender-specific mRNA targets and RNA-targeting mechanisms that control cell fate decisions in stem/progenitor cells and in adaptive responses of adult hormone-producing cell populations. The findings from this study will fully inform the field about the role of Musashi activity and mRNA translation in the control of pituitary cell plasticity and stem/progenitor cell function. Furthermore, these proposed studies relate to therapeutic approaches for endocrine and metabolic diseases, specifically caused by pituitary deficiencies. As hormone replacement strategies do not fully mimic physiological pulsatile secretion regimes, studies that promote regeneration of missing endocrine cell lineages would be a significant clinical improvement. This will positively impact gender-appropriate treatment paradigms for combined pituitary hormone deficiency, metabolic disease and pituitary tissue repair after head injury.
The proposed research is relevant to public health because it will greatly enhance our understanding of the processes that link stem/progenitor cell function to the ability of the pituitary to adapt to fluctuating hormonal demands and tissue injury (cell plasticity) in a gender-specific manner. The project is relevant to that part of NIH's mission that pertains to fundamental knowledge that should eventually lead to new diagnostic and therapeutic strategies given that deficiencies of pituitary-derived hormones cause severe morbidity. Indeed, hormone replacement strategies do not mimic physiological pulsatile secretion regimes and so manipulation of stem/progenitor function to promote regeneration of missing endocrine cell lineages would be a significant clinical improvement over current treatment options.