Jens Pahnke1,2,3* Abstract ABC Transporters B1, C1 and G2 Differentially Regulate Neuroregeneration in Mice Toni Schumacher1, Markus Krohn1,2, Jacqueline Hofrichter1, Cathleen Lange1, Jan Stenzel1, Johannes Steffen 1 , Tina Dunkelmann 1 , Kristin Paarmann 1 , Christina Fro¨ hlich1, Annekathrin Uecker1, Anne-Sophie Plath1,2, Alexandra Sommer1,2, Thomas Bru¨ ning1,2, Hans-Jochen Heinze1,2,3, 1 Neurodegeneration Research Laboratory (NRL), Department of Neurology, Universities of Rostock and Magdeburg, Magdeburg, Germany, 2 German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany, 3 Leibniz Institute for Neurobiology (LIN), Magdeburg, Germany Background: ATP-binding cassette (ABC) transporters are essential regulators of organismic homeostasis, and are particularly important in protecting the body from potentially harmful exogenous substances. Recently, an increasing number of in vitro observations have indicated a functional role of ABC transporters in the differentiation and maintenance of stem cells. Therefore, we sought to determine brain-related phenotypic changes in animals lacking the expression of distinct ABC transporters (ABCB1, ABCG2 or ABCC1). Methodology and Principal Findings: Analyzing adult neurogenesis in ABC transporter-deficient animals in vivo and neuronal stem/progenitor cells in vitro resulted in complex findings. In vivo, the differentiation of neuronal progenitors was hindered in ABC transporter-deficient mice (ABCB10/0) as evidenced by lowered numbers of doublecortin+ (236%) and calretinin+ (237%) cells. In vitro, we confirmed that this finding is not connected to the functional loss of single neural stem/ progenitor cells (NSPCs). Furthermore, assessment of activity, exploratory behavior, and anxiety levels revealed behavioral alterations in ABCB10/0 and ABCC10/0 mice, whereas ABCG20/0 mice were mostly unaffected. Conclusion and Significance: Our data show that single ABC transporter-deficiency does not necessarily impair neuronal progenitor homeostasis on the single NSPC level, as suggested by previous studies. However, loss of distinct ABC transporters impacts global brain homeostasis with far ranging consequences, leading to impaired neurogenic functions in vivo and even to distinct behavioral phenotypes. In addition to the known role of ABC transporters in proteopathies such as Parkinson’s disease and Alzheimer’s disease, our data highlight the importance of understanding the general function of ABC transporters for the brain’s homeostasis and the regeneration potential. Citation: Schumacher T, Krohn M, Hofrichter J, Lange C, Stenzel J, et al. (2012) ABC Transporters B1, C1 and G2 Differentially Regulate Neuroregeneration in Mice. PLoS ONE 7(4): e35613. doi:10.1371/journal.pone.0035613 Editor: Shu-ichi Okamoto, Sanford-Burnham Medical Research Institute, United States of America Received November 3, 2011; Accepted March 19, 2012; Published April 24, 2012 Copyright: 2012 Schumacher et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: T.S., J.H., C.L., and J.S. were supported by a study grant of the University of Rostock (Landesgraduiertenfo¨ rderung Mecklenburg-Vorpommern). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jens.pahnke@gmail.com Introduction ABC transporters arise from one of the largest known superfamily of genes, and can be found in every living organism. Most ABC transporters carry out unidirectional transmembrane transport [1]. Functionally, ABC transporters can be separated into three groups: i) importers, mostly used to import nutritious molecules and ions in prokaryotes [2,3], ii) exporters, which secrete a broad variety of dietary cytotoxic agents and thereby also numerous therapeutic drugs across biological membranes (re- viewed in [4]), and iii) a subgroup that is involved in chromatin reorganization, DNA repair, telomere maintenance and RNA trafficking [5,6,7]. Currently, 49 different human ABC genes have been identified in humans, and these are classified into seven subgroups named ABCA to ABCG based on amino acid sequence-similarities and phylogeny (reviewed in [8,9]). ABC transporters are capable of transporting a wide range of peptides, hydrophobic molecules, drugs or drug conjugates. Together, they form a chemo-defense network against xenobiotics [10]. Recently, ABC transporters have been discovered to exhibit important export functions for proteins involved in Alzheimer’s disease [11,12], with ABCC1 being of exceptional importance for the clearance of b-amyloid from the brain [13]. In addition to their role as crucial components of barriers that protect the brain from toxic substances, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (reviewed in [12,14]), these molecules also are expressed on stem cells of various tissues, and were discovered in cancer cells. Accordingly, p-glycoprotein, later identified as ABCB1, was first found to maintain cell surface permeability in a hamster cell line [15], and was later linked to chemoresistance in a multidrug resistant Chinese hamster ovary cell line [16]. Later, ABCG2 was isolated from multidrug-resistant breast cancer cells in the absence of ABCB1 [17], while ABCC1 was found to be highly expressed in PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e35613