Expression of the Rap1 guanine nucleotide exchange factor, MR-GEF, is altered in individuals with bipolar disorder.
In the rodent forebrain GABAergic neurons are generated from progenitor cells that express the transcription factors Dlx1 and Dlx2. The Rap-1 guanine nucleotide exchange factor, MR-GEF, is turned on by many of these developing GABAergic neurons. Expression of both Dlx1/2 and MR-GEF is retained in both adult mouse and human forebrain where, in human, decreased Dlx1 expression has been associated with psychosis. Using in situ hybridization studies we show that MR-GEF expression is significantly down-regulated in the forebrain of Dlx1/2 double mutant mice suggesting that MR-GEF and Dlx1/2 form part of a common signalling pathway during GABAergic neuronal development. We therefore compared MR-GEF expression by in situ hybridization in individuals with major psychiatric disorders (schizophrenia, bipolar disorder, major depression) and control individuals. We observed a significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex (DLPFC) in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder, but not in individuals with schizophrenia, major depressive disorder or in controls. Since MR-GEF encodes a Rap1 GEF able to activate G-protein signalling, we suggest that changes in MR-GEF expression could potentially influence neurotransmission.
Bithell
Angela
A
Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, United Kingdom.
Hsu
Tony
T
Kandanearatchi
Apsara
A
Landau
Sabine
S
Everall
Ian P
IP
Tsuang
Ming T
MT
Chana
Gursharan
G
Williams
Brenda P
BP
D000818:Animals; D001714:Bipolar Disorder / Q000378:metabolism*; D016022:Case-Control Studies; D015536:Down-Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis* / Q000235:genetics; D006801:Humans; D051379:Mice; D009474:Neurons; D017397:Prefrontal Cortex / Q000378:metabolism*; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid; D020663:ras Guanine Nucleotide Exchange Factors
D020662:Guanine Nucleotide Exchange Factors; C417242:RAPGEF5 protein, human; D020663:ras Guanine Nucleotide Exchange Factors; D005680:gamma-Aminobutyric Acid