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, CT1. 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 CT1 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 CT1 are prominent in CNS, skeletal muscles and intestine, where they appear earlier than GAMT. High levels of CT1 are found in epithelia.


CONCLUSIONS
Our results suggest that de novo synthesis of Cr by AGAT and GAMT, as well as cellular Cr uptake by CT1, 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.
Braissant
Olivier
O
Clinical Chemistry Laboratory, University Hospital, CH-1011 Lausanne, Switzerland. Olivier.Braissant@chuv.ch
Henry
Hugues
H
Villard
Anne-Marie
AM
Speer
Oliver
O
Wallimann
Theo
T
Bachmann
Claude
C
D000579:Amidinotransferases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003401:Creatine / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism*; D047108:Embryonic Development; D004848:Epithelium / Q000737:chemistry / Q000196:embryology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D050937:Guanidinoacetate N-Methyltransferase / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007422:Intestines / Q000737:chemistry / Q000196:embryology; D007668:Kidney / Q000737:chemistry / Q000196:embryology; D008099:Liver / Q000737:chemistry / Q000196:embryology; D026901:Membrane Transport Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000196:embryology; D009420:Nervous System / Q000737:chemistry / Q000196:embryology; D010179:Pancreas / Q000737:chemistry / Q000196:embryology; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C080679:creatine transporter; C494508:Gamt protein, rat; D050937:Guanidinoacetate N-Methyltransferase; D000579:Amidinotransferases; C020681:glycine amidinotransferase; D003401:Creatine