Differential mRNA Distribution of Components of the ERK/MAPK Signalling Cascade in the Adult Mouse Brain BARBARA DI BENEDETTO, 1,2,† CHRISTIANE HITZ, 1,† SABINE M. HO ¨ LTER, 1 RALF KU ¨ HN, 1 DANIELA M. VOGT WEISENHORN, 1,2 AND WOLFGANG WURST 1,2 * 1 GSF National Research Center for Environment and Health, Institute of Developmental Genetics, 85764 Neuherberg, Germany 2 Max-Planck-Institute of Psychiatry, Molecular Neurogenetics, 80804 Munich, Germany ABSTRACT The mitogen-activated protein kinases (MAPKs), also called extracellular signal-regulated kinases (ERKs), are a group of serine/threonine terminal protein kinases activated downstream of a pleiotrophy of transmembrane receptors. Main intracellular components of the MAPK signalling pathway are the RAF, MEK, and ERK proteins, which work in a cascade of activator and effector proteins. They regulate many fundamental cellular functions, including cell prolif- eration, cell survival, and cell differentiation by transducing extracellular signals to cytoplasmic and nuclear effectors. To reveal more details about possible activation cascades in this pathway, the present study gives a complete description of the differential expression of Braf, Mek1, Mek2, Mek5, Erk1, Erk2, Erk3, and Erk5 in the adult murine brain by way of in situ hybridization analysis. In this study, we found that each gene is widely expressed in the whole brain, except for Mek2, but each displays a very distinct expression pattern, leading to distinct interactions of the MAPK components within different regions. Most notably we found that 1) Braf and Erk3 are coexpressed in the hippocampus proper, confirming a possible functional interaction; 2) in most forebrain areas, Mek5 and Erk5 are coexpressed; and 3) in the neurogenic regions of the brain, namely, the olfactory bulb and the dentate gyrus, Braf is absent, indicating that other activator proteins have to take over its function. Despite these differences, our results show widespread coexpression of the pathway components, thereby confirming the hypothesis of redundant func- tions among several MEK and ERK proteins in some regions of the brain. J. Comp. Neurol. 500: 542–556, 2007. © 2006 Wiley-Liss, Inc. Indexing terms: Braf; Mek; Erk; in situ hybridization; neurogenesis; learning and memory Mitogen-activated protein kinases (MAPKs), also called extracellular signal-regulated kinases (ERKs), are a group of serine/threonine terminal protein kinases evolutionar- ily conserved from yeast to human. They are activated by a signalling cascade, known as the ERK/MAPK signalling pathway, that mediates the transduction of extracellular signals to cytoplasmic and nuclear effectors. ERKs regu- late a variety of cellular functions, such as cell growth, proliferation, and differentiation and cellular stress re- sponses (Pages et al., 1993; Kyriakis and Avruch, 1996; Weber et al., 1997; Refojo et al., 2005; Werry et al., 2005). Eight different ERK isoforms have been described, among which only ERK1, ERK2, ERK3, ERK4, ERK5, and ERK7 were found to be expressed in the adult rodent brain. Among these eight proteins, ERK1, ERK2, ERK3, and ERK5 belong to the canonical MAPK signalling pathway. The activation of these ERKs is mediated by their phos- phorylation on tyrosine and threonine residues via the † The first two authors contributed equally to this work. Grant sponsor: Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN); Grant number: Fo ¨rderkennzeichen 01GR0404; Grant sponsor: Eumorphia (EU); Grant number: EU/QLG2-CT-2002-00930; Grant sponsor: Volkswagen- Stiftung Foundation; Grant number: VW I/8 768; Grant sponsor: EU Mes- senger Project; Grant number: HPRN-CT-2001-00242. *Correspondence to: Wolfgang Wurst, GSF National Research Center for Environment and Health, Institute of Developmental Genetics, Ingolstaed- ter Landstrasse 1, 85764 Neuherberg, Germany. E-mail: wurst@gsf.de Received 8 June 2006; Revised 14 August 2006; Accepted 24 August 2006 DOI 10.1002/cne.21186 Published online in Wiley InterScience (www.interscience.wiley.com). THE JOURNAL OF COMPARATIVE NEUROLOGY 500:542–556 (2007) © 2006 WILEY-LISS, INC.