ORIGINAL ARTICLE SMN is required for the maintenance of embryonic stem cells and neuronal differentiation in mice Wei-Fang Chang • Jie Xu • Chia-Chun Chang • Shang-Hsun Yang • Hsin-Yang Li • Hsiu Mei Hsieh-Li • Mong-Hsun Tsai • Shinn-Chih Wu • Winston T. K. Cheng • Ji-Long Liu • Li-Ying Sung Received: 4 November 2013 / Accepted: 28 February 2014 Ó Springer-Verlag Berlin Heidelberg 2014 Abstract Survival motor neuron (SMN) is the determining factor in spinal muscular atrophy, the most common genetic cause of childhood mortality. We have previously found that SMN regulates stem cell division, proliferation and differen- tiation in Drosophila. However, it is unknown whether a similar effect exists in vertebrates. Here, we show that SMN is enriched in highly proliferative embryonic stem cells (ESCs) in mice and reduction of SMN impairs the pluripo- tency of ESCs. Moreover, we find that SMN reduction acti- vates ERK signaling and affects neuronal differentiation in vitro. Teratomas with reduced SMN grow more slowly and show weaker signals of neuronal differentiation than those with a normal level of SMN. Finally, we show that over- expression of SMN is protective for ESCs from retinoic acid- induced differentiation. Taken together, our results suggest that SMN plays a role in the maintenance of pluripotent ESCs and neuronal differentiation in mice. Keywords Survival motor neuron (SMN) Á Embryonic stem cell (ESC) Á ERK signaling Á Neuronal differentiation Introduction Spinal muscular atrophy (SMA) is characterized by the spe- cific degeneration of lower motor neurons in the spinal cord resulting in proximal muscle wasting and paralysis (Sleigh et al. 2011; Lorson et al. 2010). SMA is caused by disturbed function of the survival motor neuron (SMN) protein (Le- febvre et al. 1995). SMN and Gemin proteins form the SMN complex, which is the cellular machinery responsible for the assembly of small nuclear ribonucleoproteins (snRNPs), the major components of the spliceosome (Fischer et al. 1997; Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0743-7) contains supplementary material, which is available to authorized users. W.-F. Chang Á C.-C. Chang Á M.-H. Tsai Á S.-C. Wu Á W. T. K. Cheng Á L.-Y. Sung (&) Institute of Biotechnology, National Taiwan University, No. 81, Chang-Xiang St., Da-an District, Taipei 106, Taiwan, ROC e-mail: liyingsung@ntu.edu.tw J. Xu Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA S.-H. Yang Department of Physiology, National Cheng Kung University Medical College, Tainan 701, Taiwan, ROC H.-Y. Li Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 201, Taiwan, ROC H. M. Hsieh-Li Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, ROC W. T. K. Cheng Department of Animal Science and Biotechnology, Tunghai University, Taichung, Taiwan, ROC J.-L. Liu (&) Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK e-mail: jilong.liu@dpag.ox.ac.uk L.-Y. Sung Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan, ROC 123 Brain Struct Funct DOI 10.1007/s00429-014-0743-7