Molecular mechanisms of pituitary plasticity

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. The distinct pituitary hormone- producing cell populations are known to possess remarkable plasticity of fate. However, the underlying mechanisms that mediate pituitary cell plasticity in response to changing hormonal demands have not been established, which is a major gap in knowledge. While it is recognized that stem cell differentiation and cellular homeostasis are directed and regulated at multiple levels including gene transcription, signaling, epigenetic and chromatin remodeling, these processes appear to be particularly sensitive to mechanisms that impinge upon the control of mRNA translation. Identification of the molecular mediators that regulate cellular plasticity within pituitary hormone-producing cell lineages would present a valuable resource for therapeutic intervention to promote tissue regeneration or to oppose cancer progression. The mRNA translation control protein, Musashi, plays a critical role in mediating physiological and pathological stem cell function in many tissue types and has been shown to be broadly expressed in the adult anterior pituitary in non-stem/progenitor cell populations to modulate hormone expression. This study will focus on mechanisms by which Musashi differentially regulates distinct target mRNAs, its mode of action and contribution to cell fate plasticity and its relevance to adult human pituitary function. The long-term goal of this project is to determine the physiological mechanisms that control pituitary cell fate determination. Specifically, 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. We will also perform an unbiased assessment on the role of transcriptional and post- transcriptional control during hypothyroidism and lactation, known drivers of pituitary cell lineage plasticity. The central hypothesis is that post transcriptional mechanisms are critical for the plasticity of hormone producing cell lineages in the adult pituitary during adaptive responses to organismal stress. We expect to fully inform the field about the molecular mechanisms underpinning Musashi target mRNA-specific translational control. We will determine the relevance of Musashi-dependent control of human pituitary mRNAs under physiological and pathological conditions and will elucidate in an unbiased manner the molecular mechanisms controlling pituitary cell plasticity in response to changing hormonal demands. Wherever possible, sex will be considered a variable. Findings from this study will positively impact development of gender-specific therapeutic treatments for combined pituitary hormone deficiency and pituitary tissue repair.