ACTIVATING TRANSCRIPTION FACTOR 2 EXPRESSION IN THE ADULT HUMAN BRAIN: ASSOCIATION WITH BOTH NEURODEGENERATION AND NEUROGENESIS A. G. PEARSON, a M. A. CURTIS, b H. J. WALDVOGEL, b R. L. M. FAULL b AND M. DRAGUNOW a,c * a Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand b Department of Anatomy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand c The National Research Centre for Growth and Development, The University of Auckland, Private Bag 92019, Auckland, New Zealand Abstract—Activating transcription factor 2 (ATF2) is a mem- ber of the activator protein-1 family of transcription factors, which includes c-Jun and c-Fos. ATF2 is highly expressed in the mammalian brain although little is known about its func- tion in nerve cells. Knockout mouse studies show that this transcription factor plays a role in neuronal migration during development but over-expression of ATF2 in neuronal-like cell culture promotes nerve cell death. Using immunohisto- chemical techniques we demonstrate ATF2 expression in the normal human brain is neuronal, is found throughout the cerebral cortex and is particularly high in the granule cells of the hippocampus, in the brain stem, in the pigmented cells of the substantia nigra and locus coeruleus, and in the granule and molecular cell layers of the cerebellum. In contrast to normal cases, ATF2 expression is down-regulated in the hip- pocampus, substantia nigra pars compacta and caudate nu- cleus of the neurological diseases Alzheimer’s, Parkinson’s and Huntington’s, respectively. Paradoxically, an increase in ATF2 expression was found in the subependymal layer of Huntington’s disease cases, compared with normal brains; a region reported to contain increased numbers of proliferating progenitor cells in Huntington’s disease. We propose ATF2 plays a role in neuronal viability in the normal brain, which is compromised in susceptible regions of neurological dis- eases leading to its down-regulation. In contrast, the in- creased expression of ATF2 in the subependymal layer of Huntington’s disease suggests a role for ATF2 in some as- pect of neurogenesis in the diseased brain. © 2005 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: transcription factor, neuronal viability, sub- ependymal layer, neurogenesis. Activating transcription factor 2 (ATF2) is a constitutively expressed bZIP transcription factor and is a member of the activator protein-1 (AP-1) family. The AP-1 protein binds to the AP-1 and/or CRE/ATF motifs within the promoter re- gion of target genes causing subsequent up- or down- regulation of transcription. Target genes of ATF2 include the cell cycle proteins cyclin A (Beier et al., 2000; Shimizu et al., 1998) and cyclin D1 (Beier et al., 1999), as well as c-Jun (van Dam et al., 1995), tumor necrosis factor  (TNF; Tsai et al., 1996), transforming growth factor-2 (TGF-2; Kim et al., 1992), E-selectin (Read et al., 1997) and tyrosine hydroxylase (Suzuki et al., 2002). ATF2 is also a common target of Smad and TGF--activated kinase-1 (TAK) pathways in TGF--signaling and plays a key role in the TAK/Smad-mediated differentiation of a clonal P19 cell line into cardiomyocytes and the maturation of chick chondrocytes (Ionescu et al., 2003; Monzen et al., 2001; Sano et al., 1999). ATF2 also has intrinsic histone acetyltransferase (HAT) activity and is one of the only sequence-specific DNA-binding activators reported to date (Kawasaki et al., 2000). ATF2 is ubiquitously expressed in the brain and throughout the mammalian body (Kara et al., 1990; Maekawa et al., 1989; Takeda et al., 1991). Knockout mouse studies have demonstrated that the presence of ATF2 is required for correct neurological development and neuronal migration (Reimold et al., 1996); furthermore, ATF2 is required for resistance to apoptosis and survival of at least three different non-neuronal cancer cell lines (Hayakawa et al., 2003; Ronai et al., 1998; Zoumpourlis et al., 2000). In human tissue, ATF2 immuno-reactivity is reported to be found predominantly in white matter with very little neuronal staining (Yamada et al., 1997). In the rat brain, however, ATF2 is present in the nucleus of all neu- ronal cell populations, but not in glial cells, and its expres- sion is decreased in axotomised neurons following nerve cell lesions (Ferrer et al., 1996; Herdegen et al., 1997; Martin-Villalba et al., 1998; Robinson, 1996). ATF2 down- regulation is also associated with a corresponding in- crease in c-Jun expression in cells surviving axotomy (Buschmann et al., 1998). In addition, ATF2 is phosphor- ylated in dying pyramidal cornu ammonis (CA1) neurons, but not in surviving dentate granule cells in the rat hip- pocampus following hypoxic–ischemic insult (Walton et al., 1998). Experiments in PC12 cells have also suggested *Correspondence to: M. Dragunow, Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Tel: +64-9-373-7599x86403; fax: +64-9-373-7556. E-mail address: m.dragunow@auckland.ac.nz (M. Dragunow). Abbreviations: AD, Alzheimer’s disease; AP-1, activator protein-1; ATF2, activating transcription factor 2; CA, cornu ammonis; CN, cau- date nucleus; DAB, 3,3=-diaminobenzidine tetrahydrochloride; EP, ependymal layer; ERK, extracellular-related kinase; GFAP, glial fibril- lary acidic protein; HD, Huntington’s disease; JNK, c-Jun N-terminal kinase; PBS, phosphate-buffered saline; PBS-T, phosphate-buffered saline containing 0.2% Triton X-100; PCNA, proliferating cell nuclear antigen; PD, Parkinson’s disease; SEL, subependymal layer; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; TAK, TGF--activated kinase-1; TUNEL, terminal deoxynucleotidyl transferase-mediated dATFP biotin nick end labeling. Neuroscience 133 (2005) 437– 451 0306-4522/05$30.00+0.00 © 2005 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2005.02.029 437