SAT-119 - O-GlcNAcylation Is Essential for Pituitary Development and Postnatal Survival

Background:
O-GlcNAcylation is a dynamic post-translational modification that integrates nutrient sensing with cellular signaling. While its role has been extensively studied in metabolic tissues, its function in endocrine organ development, particularly in the pituitary gland, remains poorly understood.

Methods:
To define the role of O-GlcNAc cycling in pituitary development, we generated pituitary-specific knockout (KO) mouse models targeting O-GlcNAc transferase (Ogt) and O-GlcNAcase (Oga) using an αGSU-Cre driver active during early pituitary development. Phenotypic, molecular, and histological analyses were performed, including survival assessment, qPCR-based gene expression analysis, hormone measurements, and single-nuclei RNA sequencing.

Results:
Loss of Ogt resulted in severe embryonic or perinatal lethality, with markedly reduced recovery of KO animals, demonstrating a critical requirement for O-GlcNAcylation during early pituitary development. To assess the impact of elevated O-GlcNAcylation, we analyzed Oga-deficient mice. Oga KO mice exhibited partial viability with sex-biased lethality, incomplete penetrance, developmental abnormalities including hydrocephalus and impaired eye formation, and post-weaning mortality. Despite the absence of gross morphological defects in the pituitary, these mice displayed phenotypes consistent with endocrine dysfunction. Molecular analyses confirmed efficient loss of Oga expression across all pituitary cell types. Metabolic parameters, including body weight and fasting glucose, were not significantly altered, suggesting that lethality arises from subtle endocrine defects. Single-nuclei RNA sequencing revealed shifts in progenitor and hormone-producing cell populations, along with altered expression of key transcripts, including stress-related genes (Crhr1 and Nr3c1) in corticotrophs. These changes were accompanied by elevated corticosterone levels, indicative of increased ACTH axis activity.

Conclusion:
O-GlcNAc cycling is an essential regulator of pituitary development and survival. Both reduced and elevated O-GlcNAcylation disrupt normal development, underscoring the need for precise O-GlcNAc homeostasis in endocrine biology. These findings reveal a previously unrecognized role for O-GlcNAcylation in pituitary ontogeny and provide a framework for understanding how nutrient-sensitive signaling pathways influence endocrine development and disease.

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