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J. Biol. Chem., Vol. 282, Issue 33, 24343-24351, August 17, 2007

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Molecular Cloning of a Brain-specific, Developmentally Regulated Neuregulin 1 (NRG1) Isoform and Identification of a Functional Promoter Variant Associated with Schizophrenia^*

Wei Tan^¶, Yanhong Wang, Bert Gold^¶, Jingshan Chen, Michael Dean^¶, Paul J. Harrison^||, Daniel R. Weinberger, and Amanda J. Law^||1

From the ^||Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, United Kingdom, SAIC-Frederick and ^¶Laboratory of Genomic Diversity, NCI, National Institutes of Health, Frederick, Maryland 21702, and the Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland 20892-1385

Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants, especially rs6994992 (SNP8NRG243177). Here we have isolated and characterized full-length NRG1 type IV cDNAs from the adult and fetal human brain and identified novel splice variants of NRG1. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of 66 kDa. The transcript consists of 11 exons with an Ig-like domain, an epidermal growth factor-like (EGF) domain, a -stalk, a transmembrane domain, and a cytoplasmic "a-tail," placing it in the 1a NRG1 subclass. NRG1 type IV was not detected in any tissues except brain and a putative type IV NRG1 protein of 66 kDa was similarly brain-specific. Type IV transcripts are more abundantly expressed in the fetal brain, where, in addition to the full-length structure, two novel type IV variants were identified. In vitro luciferase-reporter assays demonstrate that the 5' promoter region upstream of type IV is functional, with differential activity associated with genetic variation at rs6994992, and that promoter competition may impact on type IV expression. Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP).

Received for publication, April 6, 2007 , and in revised form, June 1, 2007.

The nucleotide sequence(s) reported in this paper has been submitted to the Gen-Bank^TM/EBI Data Bank with accession number(s) EF372273 [GenBank] -EF372277 [GenBank] and EF517295 [GenBank] -EF517297 [GenBank] .

^* This work was supported by the Medical Research Council (MRC), United Kingdom and by Federal funds from the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research and from SAIC-Frederick under Contract NO1-CO-12400. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Table 1.

This article was selected as a Paper of the Week.

¹ An MRC, UK Career Development Fellow and NARSAD (National Alliance for Research on Schizophrenia and Depression) Young Investigator. To whom correspondence should be addressed: University of Oxford, Dept. of Psychiatry, Warneford Hospital, Oxford OX3 7JX, United Kingdom. Tel.: 301-4027810; Fax: 301-4807795; E-mail: amanda.law{at}psych.ox.ac.uk.

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