RGS6 Mediates Effects of Voluntary Running on Adult Hippocampal Neurogenesis

Gao, Yu; Gonzalez, Jose; Dong, Qiaoxiang; Kannan, Sudharsan; Hoang, Johnson T.; Eisinger, Brian E.; Pandey, Sudhir Kumar; Javadi, Sahar; Chang, Qiang; Wang, Daifeng; Overstreet-Wadiche, Linda; Zhao, Xinyu

doi:10.1016/j.celrep.2020.108114

Cited by 6 publications

(1 citation statement)

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“…1 ). In particular, alterations in RGS6 signaling and/or expression have been associated with: alcohol use disorders (rs11621871; Stewart et al, 2015 ; Chen et al, 2017 ), anxiety/depression ( Stewart et al, 2014 ), Parkinson’s disease ( Bifsha et al, 2014 ; Luo et al, 2019 ; Petyuk et al, 2021 ), Alzheimer’s disease (rs4899412; Moon et al, 2015 ), motor coordination ( Maity et al, 2012 ), adult hippocampal neurogenesis ( Gao et al, 2020 ), as well as human cataracts, mental retardation, and microcephaly (c. 1369–1 G > C; Chograni et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Protein Profiling of RGS6, a Pleiotropic Gene Implicated in Numerous Neuropsychiatric Disorders, Reveals Multi-Isoformic Expression and a Novel Brain-Specific Isoform

Ahlers‐Dannen

Yang

Spicer

et al. 2021

eNeuro

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A metanalysis identified Regulator of G protein Signaling 6 (RGS6) as one of 23 loci with pleiotropic effects on four or more human psychiatric disorders. This finding is significant as it confirms/extends the findings of numerous other studies implicating RGS6 in CNS function and pathology. RGS6 is a highly conserved member of the RGS protein family whose cellular roles are likely affected by mRNA splicing and alternative domain inclusion/exclusion. Indeed, we previously identified multiple RGS6 splice variants predicted to produce 36 distinct protein isoforms containing either long (RGS6L) or short (RGS6S) N-terminal domains, an incomplete or intact GGL domain, and 9 alternative C-termini. Unfortunately, sequence similarities between the isoforms have made it difficult to confirm their individual existence and/or to determine their unique functions. Here, we developed 3 RGS6-specific antibodies that recognize all RGS6 protein isoforms (RGS6-fl), the N-terminus of RGS6L isoforms (RGS6-L), and an 18 amino acid alternate C-terminal sequence (RGS6-18). Using these antibodies, we demonstrate that RGS6L(+GGL) isoforms, predominating in both mouse (both sexes) CNS and peripheral tissues, are most highly expressed in the CNS. We further identify 3 novel RGS6 protein bands that are larger (61, 65, and 69kDa) than the ubiquitously expressed 53-57kDa RGS6L(+GGL) proteins. Importantly, we show that the 69kDa protein is a brain-specific dephospho-form of the 65 kDa band, the first identified phosphorylated RGS6 isoform. Together, these data begin to define the functional significance behind the complexity of RGS6 gene processing and further clarifies RGS6's physiological roles by resolving tissue-specific RGS6 protein expression. 3 Significance StatementPsychiatric disorders are highly associated with polygenic variation. Consistent with this, a SNP (rs2332700) in Regulator of G protein Signaling 6 (RGS6) is linked to autism spectrum disorder, bipolar disorder, major depression, and schizophrenia. RGS6 is a highly conserved gene whose complex alternative mRNA splicing produces numerous protein isoforms with high sequence similarity, hindering their functional characterization. Therefore, while aberrant RGS6 signaling and/or expression have been linked to various neuropsychiatric disorders, it is unclear which isoforms are important. This study functionally delineates between the various RGS6 isoforms within mouse. We demonstrate that RGS6 is most highly expressed in CNS, characterize the predominant isoforms, and identify a brain-specific RGS6 protein highly expressed in brain regions associated with various psychiatric disorders.

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