SAT-118 - Loss of Amino Acid Metabolic Enzymes Causes Defects in Pituitary Gland Development

The pituitary gland is an essential organ for maintaining homeostasis and regulating physiological processes through the release of hormones. Congenital hypopituitarism (CH) is characterized by the loss of one or more pituitary hormones, with corresponding physiological disruptions. Using data from the International Mouse Phenotyping Consortium (IMPC) for embryonic lethal knockout mice lines, we identified 50 targeted genes with pituitary malformations at embryonic day of development 14.5 (e14.5). These genes represent candidate genes for CH in humans. Among those 50 candidate genes are Psph, Psat1, and Gldc, which are metabolic enzymes involved in the production of serine and the degradation of glycine. Serine and glycine can both donate carbon to the folate cycle. The folate cycle contributes carbon to the production of methionine, which can be used to generate methyl donors for epigenetic regulation, and to produce purines, which are essential for proliferation. Deficiencies in these enzymes result in decreased serine, or increased glycine, and are associated with microencephaly and neural tube defects. In the analysis of the IMPC data, we identified homozygous null embryos for Psph, Psat1, and Gldc that have malformed pituitary glands that fail to separate from the oral ectoderm. We hypothesize that 1-carbon metabolism is essential for pituitary organogenesis. To begin a functional analysis and test this hypothesis, we determined the spatial and temporal expression of these metabolic genes during embryogenesis and recovered the null alleles from cryopreservation. All three metabolic genes are more highly expressed in the ventral diencephalon than in the pituitary anterior lobe, with Gldc having striking expression in the infundibulum. After expanding each line, we generated homozygous null embryos for all three genes and observed developmental delay, craniofacial malformations, and neural tube defects as previously reported. We also confirmed the pituitary malformation at e14.5 and extended our histological analysis to earlier and later timepoints. Additional functional characterization will include hormone profiling, gene expression analysis, and single-nucleus RNA sequencing analysis at e14.5 to determine if loss of these metabolic enzymes also disrupts differentiation of pituitary progenitors, potentially resulting in hypopituitarism. With this data we will expand our knowledge on the potential genetic causes for congenital hypopituitarism and the relationship between amino acid metabolism and pituitary gland organogenesis.

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