Impaired repression at a vasopressin promoter polymorphism underlies overexpression of vasopressin in a rat model of trait anxiety.
Two inbred rat lines have been developed that show either high (HAB) or low (LAB) anxiety-related behavior. The behavioral phenotype correlates with arginine vasopressin (AVP) expression at the level of the hypothalamic paraventricular nucleus (PVN), but not supraoptic nucleus, with HAB animals overexpressing the neuropeptide in both magnocellular and parvocellular subdivisions of the PVN. We detected a number of single nucleotide polymorphisms (SNPs) in the AVP locus that differ between the HAB and LAB animals, two of which were embedded in cis-regulatory elements. The HAB-specific allele of the AVP gene promoter occurs in 1.5% of outbred Wistar rats and is more transcriptionally active in vivo, as revealed by allele-specific transcription studies in cross-mated HAB/LAB F1 animals. Interestingly, one specific SNP [A(-1276)G] conferred reduced binding of the transcriptional repressor CArG binding factor A (CBF-A) in the HAB allele, the consequent differential regulation of the AVP promoter resulting in an overexpression of AVP in vitro and in vivo. Furthermore, CBF-A is highly coexpressed in AVP-containing neurons of the PVN supporting an important role for regulation of AVP gene expression in vivo. Taken together, our results demonstrate a role for an AVP gene polymorphism and CBF-A in elevated AVP expression in the PVN of HAB rats likely to contribute to their behavioral and neuroendocrine phenotype.
Murgatroyd
Chris
C
Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
Wigger
Alexandra
A
Frank
Elisabeth
E
Singewald
Nicolas
N
Bunck
Mirjam
M
Holsboer
Florian
F
Landgraf
Rainer
R
Spengler
Dietmar
D
D000483:Alleles; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001127:Arginine Vasopressin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001859:Bone Neoplasms / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D005106:Exploratory Behavior; D005239:Fear; D005786:Gene Expression Regulation / Q000235:genetics; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000502:physiology*; D006801:Humans; D007178:Inbreeding; D018782:Maze Learning; D012516:Osteosarcoma / Q000473:pathology; D010121:Oxytocin / Q000096:biosynthesis / Q000235:genetics; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012097:Repressor Proteins / Q000502:physiology*; D012261:Ribonucleoproteins; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection
D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C121363:Hnrnpab protein, rat; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; D001127:Arginine Vasopressin; D010121:Oxytocin