Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice.
The Wfs1 gene codes for a protein with unknown function, but deficiency in this protein results in a range of neuropsychiatric and neuroendocrine syndromes. In the present study we aimed to find the functional networks influenced by Wfs1 in the hypothalamus. We performed gene expression profiling (Mouse Gene 1.0 ST Arrays) in Wfs1-deficient mice; 305 genes were differentially expressed with nominal P value<0.01. FDR (false discovery rate)-adjusted P values were significant (0.007) only for two genes: C4b (t=9.66) and Wfs1 (t=-9.03). However, several genes related to G protein signaling were very close to the FDR-adjusted significance level, such as Rgs4 (regulator of G protein signaling 4) that was downregulated (-0.34, t=-5.4) in Wfs1-deficient mice. Changes in Rgs4 and C4b expression were confirmed by QRT-PCR. In humans, Rgs4 is in the locus for bipolar disease (BPD), and its expression is downregulated in BPD. C4b is a gene related to the neurodegenerative diseases. Functional analysis including the entire data set revealed significant alterations in the canonical pathway "G protein-coupled receptor signaling." The gene expression profile in the hypothalami of the Wfs1 mutant mice was significantly similar to the profiles of following biological functions: psychological disorders, bipolar disorder, mood disorder. In conclusion, hypothalamic gene expression profile resembles with some molecular pathways functionally related to the clinical syndromes in the Wolfram syndrome patients.
Department of Physiology, Centre of Translational Medicine, Institute of Technology, University of Tartu, Tartu, Estonia. sulev.koks@ut.ee
Sulev
S
Kõks
Ursel
U
Soomets
Mario
M
Plaas
Anton
A
Terasmaa
Klari
K
Noormets
Vallo
V
Tillmann
Eero
E
Vasar
Cathy
C
Fernandes
Leonard C
LC
Schalkwyk
D000818:Animals; D004194:Disease / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics; D006160:Guanosine Triphosphate / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
D008565:Membrane Proteins; C114987:wolframin protein; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins