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Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
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2007 (English)In: BMC neuroscience (Online), ISSN 1471-2202, Vol. 8, 34- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals. RESULTS: By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1) and Proenkephalin (PENK), that together with Suppressor of cytokine signaling 2 (SOCS2), showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice. CONCLUSION: These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans.

Place, publisher, year, edition, pages
2007. Vol. 8, 34- p.
National Category
URN: urn:nbn:se:uu:diva-96114DOI: 10.1186/1471-2202-8-34ISI: 000247020700001PubMedID: 17521418OAI: oai:DiVA.org:uu-96114DiVA: diva2:170582
Available from: 2007-09-06 Created: 2007-09-06 Last updated: 2011-01-28Bibliographically approved
In thesis
1. Exploring Brain Gene Expression i Animal Models of Behaviour
Open this publication in new window or tab >>Exploring Brain Gene Expression i Animal Models of Behaviour
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The genetic basis for behavioural traits is largely unknown. The overall aim of this thesis was to find genes with importance for behavioural traits related to fear and anxiety. Microarray analysis was used to screen expression profiles of brain regions important for emotional behaviour in dogs, wolves, foxes and mice. In a first experiment, dogs and their wild ancestors the wolves were compared. Our results suggested that directed selection for behaviour might have resulted in expression changes in few genes acting on several brain functions, possibly affecting behaviour. However, the observed expressional differences were confounded with environmental effects. This was addressed in a second study on domesticated silver foxes. By correlating behaviour and brain gene expression in foxes selected for tameness to non-selected foxes raised in the same environment, we found large behavioural differences but only few genes with differential expression in the brain. Fifteen of the 40 genes showing evidence of expression difference were related to haem or haemoglobins. Further studies showed an additive genetic effect on brain gene expression, similar to the additive genetic inheritance of behaviour, indicating an involvement in domestication. Transcriptional profiling was also used for finding genes involved with the sleep disorder narcolepsy. Narcoleptic Doberman pinschers homozygous for the canarc-1 mutation were compared to their unaffected heterozygots revealing reduced expression of three genes, TAC1, PENK and SOCS2, with relevance to the narcoleptic phenotype. Finally gene expression was investigated in relation to anxiety-related traits in a mouse model. Surprisingly, as in the fox study, genes coding for haemoglobins indicated differential expression in the brain between animals with different anxiety levels. Our combined results suggest that genes like haemoglobins, best known for their function in oxygen transport in blood, may also participate in brain functions related to decreased anxiety in domestic animals.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 46 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 329
Biology, behavioural genetics, gene expression, brain, microarray analysis, domestication, animal model, haem, Canis familiaris, Vulpes vulpes, Mus musculus, Biologi
urn:nbn:se:uu:diva-8177 (URN)978-91-554-6948-1 (ISBN)
Public defence
2007-09-27, Zootissalen, Zoologiska institutionen, EBC, Norbyvägen 16, Uppsala, 13:00
Available from: 2007-09-06 Created: 2007-09-06Bibliographically approved

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Jazin, Elena
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