Nutrient sensing O-GlcNAcylation in pituitary development

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 DESCRIPTION (provided by applicant): Due to the trend of global growing sugar consumption, determining the interplay between diet and pre- and post-natal development is emerging as a critical area for future generations. Currently, the average American eats around 22 teaspoons of added sugar every day (~30 sugar cubes/day hidden in foods). This modern glucose-rich diet correlates with an increase in the prevalence of obesity, diabetes and others metabolic syndromes. Therefore, understanding what happens when sugars are metabolized will be of utmost importance for public health. O-GlcNAcylation is one of the key components of diet-responsive signaling. This unique glucose rheostat is a ubiquitous and dynamic post-translational modification of intracellular proteins. Two key enzymes drive O- GlcNAc cycling: the O-GlcNAc transferase adds the modification and the O-GlcNAcase (OGA) removes it. Because this post-translational modification is directly dependent on glucose input, depleting OGA creates an artificial and constant hyperglycemia-induced O-GlcNAcylation state. Our lab has developed Oga knockout (KO) cellular and mouse models, which we can use to decipher the impact of high carbohydrate concentration on embryonic development. My preliminary data strongly supports that O-GlcNAcylation acts as a sensor of sugar levels for key signaling pathways during embryogenesis. In fact, the Oga brain KO mice exhibit a developmental delay, which is noticeable in adult animals. We have also uncovered a striking delay in pituitary development that likely has consequences on key fetal hormones secretion. Deregulation of OTX2, a homeobox protein critical for pituitary development, has been observed in the Oga KO. Based on our preliminary data, we hypothesize that the excess O-GlcNAcylation impacts the development of the anterior pituitary, by principally modifying OTX2 functions and networks, and triggers severe developmental defects. Using our model systems, we will define the involvement of O-GlcNAc cycling in the development of the neuroendocrine system, which supports proper body development. We will first assess the impact of O- GlcNAcylation on pituitary development and the subsequent hormone secretion (K99), focusing on OTX2 expression, processing, and activity. In parallel, we will target Oga KO in a pituitary-lineages-specific manner to observe secretory-cell specific effect. In the second part of this project (R00), we will define the influece of high sugar consumption on neuroendocrine function through O-GlcNAcylation. This goal in mind, we will pregnant mice to a high carbohydrate diet and analyze pre- and post-natal development and observe the impact of fructose and/or glucose on O-GlcNAcylation and OTX2 functions. Finally, we will differentiate in vitro supplement mice hormone-deficiency with in vitro differentiated pituitary cells under varied nutrient conditions. We are suggesting that O-GlcNAcylation needs to be taken into account when analyzing, deciphering and treating neuroendocrine pathologies like developmental delay and neuroendocrine tumors. Moreover, this study will be a new approach to understand how diet impacts hormone secretion during embryonic development as well as later in life.