Mice carrying a human GLUD2 gene recapitulate aspects of human transcriptome and metabolome development.
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.
Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China; University of Chinese Academy of Sciences, 100049 Beijing, China;
Qian
Q
Li
Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China;
Song
S
Guo
Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China;
Xi
X
Jiang
Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
Jaroslaw
J
Bryk
Max Planck Institute of Molecular Cell Biology and Genetics, D-01307 Dresden, Germany;
Ronald
R
Naumann
Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
Wolfgang
W
Enard
Institute for Advanced Biosciences, Keio University, 997-0035 Tsuruoka, Yamagata, Japan;
Masaru
M
Tomita
Institute for Advanced Biosciences, Keio University, 997-0035 Tsuruoka, Yamagata, Japan;
Masahiro
M
Sugimoto
Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China; Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany; Skolkovo Institute for Science and Technology, 143025 Skolkovo, Russia khaitovich@eva.mpg.de paabo@eva.mpg.de.
Philipp
P
Khaitovich
Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany; khaitovich@eva.mpg.de paabo@eva.mpg.de.
Svante
S
Pääbo
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002952:Citric Acid Cycle / Q000502:physiology*; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D055442:Metabolome / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity; D059467:Transcriptome / Q000502:physiology*
D017470:Receptors, Glutamate; D011994:Recombinant Proteins; C107913:glutamate receptor delta 2; D018698:Glutamic Acid; D005969:Glutamate Dehydrogenase; C521120:GLUD2 protein, human
GLUD2; brain metabolism; human evolution