Differential Glucose Transporter Expression during Perinatal and Postnatal Erythropoiesis

Abstract

Glucose is a major source of energy for living organisms and its transport in vertebrates is a universally conserved property. Of all cell lineages, human erythrocytes express the highest level of the Glut1 glucose transporter with >200,000 molecules/cell. However, we recently reported that erythrocyte Glut1 expression is a specific trait of vitamin C-deficient mammalian species, comprising only higher primates, guinea pigs and fruit bats (Montel-Hagen et al., Cell, 2008). We now show that in all other tested mammals, including mice, rats, dogs and cows, Glut1 is in fact transiently expressed in erythrocytes during the neonatal period. This is in marked contrast with humans, where Glut1 is present at equivalently high levels on both neonatal and adult RBC. In mice, we found that Glut1 expression was not associated with primitive erythropoiesis but was highly expressed during definitive fetal erythropoiesis. Indeed, this transporter was present at significantly earlier stages of erythropoiesis in fetal spleen and liver than immediately following birth. It was therefore important to determine whether erythrocyte Glut1 expression in mice is specifically associated with fetal erythropoiesis or alternatively, is common to any physiological state where an extensive erythropoiesis is provoked. Induction of a hemolytic anemia in adult mice resulted in a massive erythropoiesis with significant increase in glucose uptake but notably, Glut1 was not detected. Rather, in these conditions as well as following birth, Glut4, an insulin-sensitive transporter previously thought to be responsible for glucose uptake in muscle and adipose tissue, was highly expressed. Following birth, the concomitant repression of Glut1 and induction of Glut4 was associated with a significantly augmented ratio of the Sp3 to Sp1 zinc-finger transcription factors. Thus, in contrast to humans, murine Glut1 is highly expressed during definitive erythropoiesis and is then downregulated at birth. Further erythroid development is characterized by the upregulation of a distinct glucose transporter, Glut4. Expression of distinct glucose transporters in nonhuman erythrocytes, regulated at the transcriptional level, therefore characterizes different states of erythroid development and differentiation.