(482.42) Delineating the role of gldc in nephron patterning during kidney development

Poster Board Number: C157
Introduction: AAA has separate poster presentation times for odd and even posters.
Odd poster #s – 10:15 am – 11:15 am
Even poster #s – 11:15 am – 12:15 pm

Nicole Weaver (University of Notre Dame), Rebecca Wingert (University of Notre Dame)

Glycine is a simple amino acid that is vital to the proper functioning of the body, but its roles during ontogeny are not well understood. Glycine levels are precisely regulated through the glycine cleavage system (GCS), a complex molecular machine that produces one-carbon units for later metabolism and folate production. Elevated glycine levels due to congenital mutations in GCS components, such as glycine dehydrogenase (gldc), cause devastating human birth defects and the rare disease nonketotic hyperglycinemia (NKH). NKH patients suffer from pleiotropic symptoms including seizures, apnea, lethargy, severe mental retardation, and early death; therefore, it is imperative to elucidate the downstream pathological mechanisms of glycine accumulation, which are to date largely unknown. Our lab, and others, have recently reported gldc deficiency and glycine addition cause developmental changes in various tissues. Here, we interrogate the role of gldc in renal ontogeny. Whole mount in situ hybridization (WISH) revealed that gldc transcripts were highly expressed in multiple tissues, including the central nervous system and embryonic kidney, recapitulating both mouse and human expression studies. We found that formation of nephron cell populations in the kidney was disrupted in gldc deficient and glycine treated embryos, where the distal early (DE) segment was increased at the expense of the distal late (DL) segment. These alterations led us to hypothesize that gldc is essential for distal segment patterning, a process that is regulated by interplay between the Iroquois (irx) transcription factors and transcription factor AP-2a (tfap2a). To test this hypothesis, we have begun to analyze the spatiotemporal expression domains of irx3b and irx1a, which are conserved regulators of intermediate and distal segment development. Using WISH, we found that gldc deficient and glycine treated animals exhibited an increase in the expression domain of irx1a, coinciding with the changes in DE specific solute transporter gene expression patterns. Taken together, these studies indicate that gldc has essential roles in regulating segment pattern during distal nephron development.