TY - JOUR
T1 - Mice carrying a human GLUD2 gene recapitulate aspects of human transcriptome and metabolome development
AU - Li, Qian
AU - Guo, Song
AU - Jiang, Xi
AU - Bryk, Jaroslaw
AU - Naumann, Ronald
AU - Enard, Wolfgang
AU - Tomita, Masaru
AU - Sugimoto, Masahiro
AU - Khaitovich, Philipp
AU - Pääbo, Svante
N1 - Funding Information:
We thank Rowina Voigtländer and the staff of the Max Planck Institute for Evolutionary Anthropology's animal facility for expert mouse care; Wulf Hevers and Ines Bliesener for help in preparation of mouse samples; Dr. H. R. Zielke and Dr. J. Dai for providing the human samples; C. Lian, H. Cai, and X. Zheng for providing the macaque samples; J. Boyd-Kirkup for editing the manuscript; Z. He for assistance; and all members of the Comparative Biology Group in Shanghai for helpful discussions and suggestions. This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders; the Netherlands Brain Bank; the Chinese Brain Bank Center; the Suzhou Drug Safety Evaluation and Research Center; the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDB13010200 to P.K.); the National Natural Science Foundation of China (Grants 91331203 and 31420103920 to P.K.); the National One Thousand Foreign Experts Plan (Grant WQ20123100078 to P.K.); the National Natural Science Foundation of China (Grant 31401065 to S.G.); the Max Planck Society; and the Paul G. Allen Family Foundation (S.P.)
PY - 2016/5/10
Y1 - 2016/5/10
N2 - Whereas all mammals have one glutamate dehydrogenase gene (GLUD1), humans and apes carry an additional gene (GLUD2), which encodes an enzyme with distinct biochemical properties. We inserted a bacterial artificial chromosome containing the human GLUD2 gene into mice and analyzed the resulting changes in the transcriptome and metabolome during postnatal brain development. Effects were most pronounced early postnatally, and predominantly genes involved in neuronal development were affected. Remarkably, the effects in the transgenic mice partially parallel the transcriptome and metabolome differences seen between humans and macaques analyzed. Notably, the introduction of GLUD2 did not affect glutamate levels in mice, consistent with observations in the primates. Instead, the metabolic effects of GLUD2 center on the tricarboxylic acid cycle, suggesting that GLUD2 affects carbon flux during early brain development, possibly supporting lipid biosynthesis.
AB - Whereas all mammals have one glutamate dehydrogenase gene (GLUD1), humans and apes carry an additional gene (GLUD2), which encodes an enzyme with distinct biochemical properties. We inserted a bacterial artificial chromosome containing the human GLUD2 gene into mice and analyzed the resulting changes in the transcriptome and metabolome during postnatal brain development. Effects were most pronounced early postnatally, and predominantly genes involved in neuronal development were affected. Remarkably, the effects in the transgenic mice partially parallel the transcriptome and metabolome differences seen between humans and macaques analyzed. Notably, the introduction of GLUD2 did not affect glutamate levels in mice, consistent with observations in the primates. Instead, the metabolic effects of GLUD2 center on the tricarboxylic acid cycle, suggesting that GLUD2 affects carbon flux during early brain development, possibly supporting lipid biosynthesis.
KW - Brain metabolism
KW - GLUD2
KW - Human evolution
UR - http://www.scopus.com/inward/record.url?scp=84966377314&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84966377314&partnerID=8YFLogxK
U2 - 10.1073/pnas.1519261113
DO - 10.1073/pnas.1519261113
M3 - Article
C2 - 27118840
AN - SCOPUS:84966377314
SN - 0027-8424
VL - 113
SP - 5358
EP - 5363
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -