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Molecular and Cellular Biology, April 2005, p. 3019-3026, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.3019-3026.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Imprinted Nesp55 Influences Behavioral Reactivity to Novel Environments

Antonius Plagge,1 Anthony R. Isles,2 Emma Gordon,1 Trevor Humby,2 Wendy Dean,1 Sabine Gritsch,3 Reiner Fischer-Colbrie,3 Lawrence S. Wilkinson,2 and Gavin Kelsey1*

Laboratory of Developmental Genetics and Imprinting,1 Laboratory of Cognitive and Behavioral Neuroscience, The Babraham Institute, Cambridge, United Kingdom,2 Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria3

Received 29 October 2004/ Returned for modification 7 December 2004/ Accepted 18 January 2005

Genomic imprinting results in parent-of-origin-dependent monoallelic expression of selected genes. Although their importance in development and physiology is recognized, few imprinted genes have been investigated for their effects on brain function. Gnas is a complex imprinted locus whose gene products are involved in early postnatal adaptations and neuroendocrine functions. Gnas encodes the stimulatory G-protein subunit Gs{alpha} and two other imprinted protein-coding transcripts. Of these, the Nesp transcript, expressed exclusively from the maternal allele, codes for neuroendocrine secretory protein 55 (Nesp55), a chromogranin-like polypeptide associated with the constitutive secretory pathway but with an unknown function. Nesp is expressed in restricted brain nuclei, suggesting an involvement in specific behaviors. We have generated a knockout of Nesp55 in mice. Nesp55-deficient mice develop normally, excluding a role of this protein in the severe postnatal effects associated with imprinting of the Gnas cluster. Behavioral analysis of adult Nesp55 mutants revealed, in three separate tasks, abnormal reactivity to novel environments independent of general locomotor activity and anxiety. This phenotype may be related to prominent Nesp55 expression in the noradrenergic locus coeruleus. These results indicate a role of maternally expressed Nesp55 in controlling exploratory behavior and are the first demonstration that imprinted genes affect such a fundamental behavior.

* Corresponding author. Mailing address: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, United Kingdom. Phone: 44 (0) 1223 496332. Fax: 44 (0) 1223 496022. E-mail: gavin.kelsey{at}bbsrc.ac.uk.

Molecular and Cellular Biology, April 2005, p. 3019-3026, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.3019-3026.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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