Creatine synthesis and transport during rat embryogenesis: Spatiotemporal expression of AGAT, GAMT and CT1

Background: Creatine ( Cr) is synthesized by a two- step mechanism involving arginine: glycine amidinotransferase ( AGAT) and guanidinoacetate methyltransferase ( GAMT), and is taken up by cells through a specific Cr transporter, CTl. Recently, genetic defects of this pathway have been described, that lead to Cr deficiency, neurological symptoms in early infancy and severe neurodevelopmental delay. To investigate the involvement of Cr synthesis and uptake pathways during embryonic development, we determined the spatiotemporal expression of AGAT, GAMT and CTl during the rat embryogenesis, at the mRNA and protein level. Results: We show that AGAT and GAMT are expressed in hepatic primordium as soon as 12.5 days, then progressively acquire their adult pattern of expression, with high levels of AGAT in kidney and pancreas, and high levels of GAMT in liver and pancreas. AGAT and CTl are prominent in CNS, skeletal muscles and intestine, where they appear earlier than GAMT. High levels of CTl are found in epithelia. Conclusion: Our results suggest that de novo synthesis of Cr by AGAT and GAMT, as well as cellular Cr uptake by CTl, are essential during embryonic development. This work provides new clues on how creatine can be provided to developing tissues, and suggests that Cr deficiencies might induce irreversible damages already in utero, particularly on the nervous system.