Transgenic Mice Carrying GLUD2 as a Tool for Studying the Expressional and the Functional Adaptation of this Positive Selected Gene in Human Brain Evolution

Abstract

Human evolution is characterized by brain expansion and up-regulation of genes involved in energy metabolism and synaptic transmission, including the glutamate signaling pathway. Glutamate is the excitatory transmitter of neural circuits sub-serving cognitive functions, with glutamate-modulation of synaptic plasticity being central to learning and memory. GLUD2 is a novel positively-selected human gene involved in glutamatergic transmission and energy metabolism that underwent rapid evolutionary adaptation concomitantly with prefrontal cortex enlargement. Two evolutionary replacements (Gly456Ala and Arg443Ser) made hGDH2 resistant to GTP inhibition and allowed distinct regulation, enabling enhanced enzyme function under high glutamatergic system demands. GLUD2 adaptation may have contributed to unique human traits, but evidence for this is lacking. GLUD2 arose through retro-positioning of a processed GLUD1 mRNA to the X chromosome, a DNA replication mechanism that typically generates pseudogenes. However, by finding a suitable promoter, GLUD2 is thought to have gained expression in nerve and other tissues, where it adapted to their particular needs. Here we generated GLUD2 transgenic (Tg) mice by inserting in their genome a segment of the human X chromosome, containing the GLUD2 gene and its putative promoter. Double IF studies of Tg mouse brain revealed that the human gene is expressed in the host mouse brain in a pattern similar to that observed in human brain, thus providing credence to the above hypothesis. This expressional adaptation may have conferred novel role(s) on GLUD2 in human brain. Previous observations, also in GLUD2 Tg mice, generated and studied independently, showed that the non-redundant function of hGDH2 is markedly activated during early post-natal brain development, contributing to developmental changes in prefrontal cortex similar to those attributed to human divergence. Hence, GLUD2 adaptation may have influenced the evolutionary course taken by the human brain, but understanding the mechanism(s) involved remains challenging.

A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling

“…Yet there are examples in which this technique appears reliable. Expression of human glutamate dehydrogenase 2 in the mouse results in the same protein localization [46], and the gene expression secondary to glutamate dehydrogenase 2 expression mirrors that found in humans [47].…”

Crystal structure of glutamate dehydrogenase 2, a positively selected novel human enzyme involved in brain biology and cancer pathophysiology

“…Interestingly, because of the extensive structural similarity of hGDH1 and hGDH2 which are often co‐expressed in the same cell type (Plaitakis et al., 2019), the possibility of GDH hetero‐hexamer formation from various combinations of the isoenzymes cannot be ruled out. Future investigations towards this direction will explore GDH oligomerization pathways.…”

“…Furthermore, the structure-based interpretation of the properties of a hGDH1 Met415Leu/Gly456Ala/Arg443Ser/ Arg470His mutant, revealed the key role of the residue 470 for the ADP affinity of hGDH. Interestingly, because of the extensive structural similarity of hGDH1 and hGDH2 which are often co-expressed in the same cell type (Plaitakis et al, 2019), the possibility of GDH hetero-hexamer formation from various combinations of the isoenzymes cannot be ruled out. Future investigations towards this direction will explore GDH oligomerization pathways.…”

“…Even in human tissues where the two isoenzymes coexist, their cellular distribution and inferred metabolic roles are often different (Zaganas et al., 2012). For example in contrast to the mainly astrocytic localization of hGDH1, hGDH2 is found in both human astrocytes and neurons, where it is thought to contribute to glutamate handling, both as a neurotransmitter and as a metabolic intermediate (Plaitakis et al., 2019). The importance of hGDH2 in human physiology and pathophysiology is further underscored by recent evidence concerning its putative role in early nervous system development (Li et al., 2016), neurodegenerative processes (Bao et al., 2009; Plaitakis et al., 2010; Wang et al., 2014) and oncogenesis (Chen et al., 2014; Franceschi et al., 2018).…”

Glutamate-specific gene linked to human brain evolution enhances synaptic plasticity and cognitive processes

“… 10 Its genesis may relate to selective pressures on the genome to enhance excitatory mechanisms required for the expansion of the cognitive capabilities of the Hominidae. 12 …”