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Transcriptional Regulator Zeb2 Is Essential for Bergmann Glia Development

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Transcriptional Regulator Zeb2 Is Essential for Bergmann Glia Development This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Development/Plasticity/Repair Transcriptional Regulator Zeb2 is Essential for Bergmann Glia Development Li He1, Kun Yu1, Fanghui Lu2, Jiajia Wang3, Laiman N. Wu2, Chuntao Zhao2, Qianmei Li1, Xianyao Zhou1, Hanmin Liu1, Dezhi Mu1, Mei Xin2, Mengsheng Qiu4,5 and Q. Richard Lu2 1Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China 2Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA 3Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. 4Institute of Developmental and Regenerative Biology, Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life Sciences, Hangzhou Normal University, Hangzhou, 310029, China 5Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky 40292, USA DOI: 10.1523/JNEUROSCI.2674-17.2018 Received: 13 September 2017 Revised: 25 December 2017 Accepted: 5 January 2018 Published: 11 January 2018 Author contributions: L.H., D.M., M.X., and Q.R.L. designed research; L.H., K.Y., F.L., J.W., L.W., and C.Z. performed research; K.Y., J.W., L.W., Q.L., X.Z., H.L., D.M., M.Q., and Q.R.L. analyzed data; F.L., C.Z., Q.L., X.Z., H.L., and M.Q. contributed unpublished reagents/analytic tools; M.X. and Q.R.L. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. Authors would like to thank Guojiao Huang and Lingli Xu for technical support. We thank Dr. Edward Hurlock for comments and Dr. Danny Huylebroeck for Zeb2 floxed mice. This study was funded in part by grants from the US National Institutes of Health R01NS072427 and R01NS075243 to QRL and the National Multiple Sclerosis Society (NMSS-4727) to QRL. Correspondence: Dr. Q. Richard Lu, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Email: [email protected] Tel: 513-636-7684; Fax: 513-803-0783 Cite as: J. Neurosci ; 10.1523/JNEUROSCI.2674-17.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors 1 2 Transcriptional Regulator Zeb2 is Essential for Bergmann Glia Development 3 4 Li He1*, Kun Yu1*, Fanghui Lu2, Jiajia Wang3, Laiman N. Wu2, Chuntao Zhao2, Qianmei Li1, 5 Xianyao Zhou1, Hanmin Liu1, Dezhi Mu1, Mei Xin2, Mengsheng Qiu4, and Q. Richard Lu2# 6 7 1Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry 8 of Education, Department of Pediatrics, West China Second University Hospital, Sichuan 9 University, Chengdu 610041, China 10 2Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, 11 Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, 12 USA 13 3Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer 14 Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. 15 4Institute of Developmental and Regenerative Biology, Key Laboratory of Organ 16 Development and Regeneration of Zhejiang Province, College of Life Sciences, Hangzhou 17 Normal University, Hangzhou, 310029, China; Department of Anatomical Sciences and 18 Neurobiology, University of Louisville, Louisville, Kentucky 40292, USA 19 20 21 22 23 24 Number of pages: 27; Number of Figures:7; Number of words for Abstract: 200; Number of 25 words for Introduction:649; Number of words for Discussion:1420 26 27 28 Running title: Zeb2 control of Bergmann glia formation 29 30 Conflict of Interest: 31 The authors declare no competing financial interests. 32 33 * These authors contributed equally to this work. 34 35 36 Acknowledgments: 37 Authors would like to thank Guojiao Huang and Lingli Xu for technical support. We 38 thank Dr. Edward Hurlock for comments and Dr. Danny Huylebroeck for Zeb2 floxed 39 mice. This study was funded in part by grants from the US National Institutes of Health 40 R01NS072427 and R01NS075243 to QRL and the National Multiple Sclerosis Society 41 (NMSS-4727) to QRL. 42 43 Correspondence: Dr. Q. Richard Lu, Cincinnati Children’s Hospital Medical Center, 44 Cincinnati, OH 45229, USA; Email: [email protected] Tel: 513-636-7684; Fax: 513- 45 803-0783 46 47 Abstract 48 49 50 51 Bergmann glia facilitate granule neuron migration during development and maintain the 52 cerebellar organization and functional integrity. At present, molecular control of Bergmann 53 glia specification from cerebellar radial glia is not fully understood. In this report, we show 54 that Zeb2 (a.k.a. Sip1 or Zfhx1b), a Mowat-Wilson-syndrome-associated transcriptional 55 regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the 56 cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in 57 Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and 58 locomotion defects. In developing Zeb2-mutant cerebella, inward migration of granule 59 neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial 60 glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast, Zeb2 61 ablation in granule neuron precursors or oligodendrocyte progenitors does not affect 62 Bergmann glia formation, despite myelination deficits caused by Zeb2 mutation in the 63 oligodendrocyte lineage. Transcriptome profiling identified that Zeb2 regulates a set of 64 Bergmann glia-related genes and FGF, NOTCH and TGFβ/BMP signaling pathway 65 components. Our data reveal that Zeb2 acts as an integral regulator of Bergmann glia 66 formation ensuring maintenance of cerebellar integrity, suggesting that Zeb2 dysfunction in 67 Bergmann gliogenesis might contribute to motor deficits in Mowat-Wilson syndrome. 68 69 2 70 71 Significance Statement 72 73 Bergmann glia are essential for proper cerebellar organization and functional circuitry, 74 however, the molecular mechanisms that control the specification of Bergmann glia remain 75 elusive. Here, we show that transcriptional factor Zeb2 is highly expressed in mature 76 Bergmann glia, but not in cerebellar astrocytes. The mice lacking Zeb2 in cerebellar radial 77 glia, but not oligodendrocyte progenitors or granular neuron progenitors, exhibit severe 78 defects in Bergmann glia formation. The orderly radial scaffolding formed by Bergmann glial 79 fibers critical for cerebellar lamination was not established in Zeb2 mutants, displaying motor 80 behavior deficits. This finding demonstrates a previously unrecognized critical role for Zeb2 81 in Bergmann glia specification, and points to an important contribution of Zeb2 dysfunction 82 to cerebellar motor disorders in Mowat-Wilson syndrome. 83 84 85 86 3 87 Introduction 88 89 The cerebellum is essential for smoothly coordinated vestibular, motor and cognitive function. 90 Cerebellar malformation disrupts not only balance and locomotion (Ito, 2006), but also 91 sensory-motor learning, speech, and spatial memory (Boyden et al., 2004; Buckner, 2013). 92 The cerebellar cortex consists of three layers: an outer molecular layer (ML), the middle 93 Purkinje cell layer, and an inner granular layer (IGL). The IGL neurons, the most prevalent 94 cerebellar neurons, are derived from granule neuron precursors (GNPs), which are 95 peripherally located in the external germinal layer (EGL) during early postnatal stages. The 96 Purkinje cell layer contains the soma of Purkinje neurons and Bergmann glia. 97 Bergmann glia are “specialized” radial astrocytes in the cerebellar cortex, where their 98 cell bodies are located in the Purkinje cell layer and processes extend into the ML layer, 99 terminating at the pial surface (Hatten, 1999; Wang and Zoghbi, 2001). During early 100 postnatal stages, GNPs proliferate in the EGL and migrate radially along the Bergmann glial 101 process in an outside-in manner to form mature IGL neurons in the cerebellum (Sillitoe and 102 Joyner, 2007; Millen and Gleeson, 2008). Bergmann glia also interact with Purkinje neurons 103 and facilitate synaptic transmission and maintenance (Bellamy, 2006; Lopez-Bayghen et al., 104 2007). Impairment of Bergmann-glia mediated GNP migration disrupts the laminar structure 105 of the cerebellum and synaptic connections and thereby disrupts cerebellar functions (Roussel 106 and Hatten, 2011; Buckner, 2013). 107 Bergmann glia are derived from radial glia in the cerebellar ventricular zone through 108 retraction of apical processes (Yuasa, 1996; Yamada and Watanabe, 2002). During the radial- 109 to-Bergmann glial transition, which occurs between mouse embryonic days (E) 14.5 and 18.5, 110 Bergmann glia precursors maintain the radial basal processes and relocate their soma from 111 the ventricular zone to the future Purkinje cell layer, and subsequently differentiate into 112 mature Bergmann glia around P6 (Yuasa, 1996; Yamada and Watanabe, 2002). Bergmann 4 113 glial radial fibers facilitate inward migration of
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