Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction.
Glucose transporter isoform-3 (GLUT3) is the trophoblastic facilitative glucose transporter. To investigate the role of this isoform in embryonic development, we created a novel GLUT3-null mouse and observed arrested early embryonic development and loss at neurulation stage when both alleles were mutated. This loss occurred despite the presence of other related isoforms, particularly GLUT1. In contrast, when a single allele was mutated, despite increased embryonic cell apoptosis, adaptive changes in the subcellular localization of GLUT3 and GLUT1 in the preimplantation embryo led to postimplantation survival. This survival was compromised by decreased GLUT3-mediated transplacental glucose transport, causing late-gestation fetal growth restriction. This yielded young male and female adults demonstrating catch-up growth, with normal basal glucose, insulin, insulin-like growth factor-I and IGF-binding protein-3 concentrations, fat and lean mass, and glucose and insulin tolerance. We conclude that GLUT3 mutations cause a gene dose-dependent early pregnancy loss or late-gestation fetal growth restriction despite the presence of embryonic and placental GLUT1 and a compensatory increase in system A amino acid placental transport. This critical life-sustaining functional role for GLUT3 in embryonic development provides the basis for investigating the existence of human GLUT3 mutations with similar consequences during early pregnancy.
Ganguly
Amit
A
Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. sdevaskar@mednet.ucla.edu
McKnight
Robert A
RA
Raychaudhuri
Santanu
S
Shin
Bo-Chul
BC
Ma
Zhigui
Z
Moley
Kelle
K
Devaskar
Sherin U
SU
D000022:Abortion, Spontaneous / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001755:Blastocyst / Q000378:metabolism / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000502:physiology; D047108:Embryonic Development / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000502:physiology; D005260:Female; D005951:Glucose Tolerance Test; D051274:Glucose Transporter Type 3 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010920:Placenta / Q000033:anatomy & histology / Q000378:metabolism / Q000502:physiology; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001786:Blood Glucose; D051274:Glucose Transporter Type 3; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; C495689:Slc2a3 protein, mouse; D007334:Insulin-Like Growth Factor I