Muons penetrate much further than X-rays, they do essentially zero damage, and they are provided for free by the cosmos.
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Edited by Joshua M. Akey, University of Washington, Seattle, WA, and accepted by the Editorial Board April 1, 2016 (received for review September 28, 2015)
Significance
A novel version of the glutamate dehydrogenase gene, GLUD2, evolved in the common ancestors of humans and apes. Based on sequence and expression pattern, GLUD2 has been suggested to play a role in glutamate metabolism in human and ape brains. We have generated transgenic mice carrying a human GLUD2 gene. Analysis of transcriptome and metabolome changes induced by GLUD2 in the cerebral cortex revealed no changes in glutamate concentration but instead changes to metabolic pathways centering on the TCA cycle during early postnatal development. These changes mirrored differences seen between human and macaque during cortex development, suggesting that GLUD2 may play a role during brain development in apes and humans, possibly by providing precursors for the biosynthesis of lipids.
Abstract
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.
Footnotes
↵1Q.L. and S.G. contributed equally to this work.
↵2Present address: School of Applied Sciences, University of Huddersfield, HD1 3DH Huddersfield, UK.
↵3Present address: Department of Biology II, Ludwig Maximilians University, 82152 Martinsried, Germany.
- ↵4To whom correspondence may be addressed. Email: khaitovich{at}eva.mpg.de or paabo{at}eva.mpg.de.
Author contributions: W.E., P.K., and S.P. designed research; X.J., J.B., R.N., and M.S. performed research; W.E., M.T., and M.S. contributed reagents/analytic tools; Q.L. and S.G. analyzed data; and Q.L., P.K., and S.P. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. J.M.A. is a guest editor invited by the Editorial Board.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE80122).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1519261113/-/DCSupplemental.
Freely available online through the PNAS open access option.
Survey of GLUD2 function using transgenic mice
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