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X-Linked Microtubule-Associated Protein, Mid1, Regulates Axon Development

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X-Linked Microtubule-Associated Protein, Mid1, Regulates Axon Development X-linked microtubule-associated protein, Mid1, regulates axon development Tingjia Lua,b,1, Renchao Chena,b,1,2, Timothy C. Coxc,d, Randal X. Moldriche, Nyoman Kurniawanf, Guohe Tana, Jo K. Perryg, Alan Ashworthg, Perry F. Bartlette,LiXua, Jing Zhanga, Bin Lua, Mingyue Wua,b, Qi Shena, Yuanyuan Liua,b, Linda J. Richardse,h, and Zhiqi Xionga,2 aInstitute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; bUniversity of Chinese Academy of Sciences, Shanghai 200031, China; cDepartment of Pediatrics, University of Washington, Seattle, WA 98105; dDepartment of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia; eQueensland Brain Institute, fCentre for Advanced Imaging, and hSchool of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072, Australia; and gBreakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW7 3RP, United Kingdom Edited by Yuh Nung Jan, Howard Hughes Medical Institute, University of California, San Francisco, CA, and approved October 8, 2013 (received for review March 25, 2013) Opitz syndrome (OS) is a genetic neurological disorder. The gene axonal growth and branch formation whereas down-regulation of responsible for the X-linked form of OS, Midline-1 (MID1), encodes Mid1 in the developing cortex accelerated callosal axon growth an E3 ubiquitin ligase that regulates the degradation of the cata- and altered the projection pattern of callosal axons. In addition, lytic subunit of protein phosphatase 2A (PP2Ac). However, how a similar defect of axon development was observed in Mid1 Mid1 functions during neural development is largely unknown. knockout (KO) mice. Consistent with an observed increase in In this study, we provide data from in vitro and in vivo experi- PP2Ac levels following loss of Mid1, knockdown of PP2Ac in ments suggesting that silencing Mid1 in developing neurons pro- Mid1-depleted cells rescued the axonal phenotypes both in vitro motes axon growth and branch formation, resulting in a disruption and in vivo. Together, we report the importance of Mid1-regu- of callosal axon projections in the contralateral cortex. In addition, lated PP2Ac turnover in axon development and provide a possi- a similar phenotype of axonal development was observed in the ble mechanism underlying the pathological outcomes observed Mid1 knockout mouse. This defect was largely due to the accumu- in OS. lation of PP2Ac in Mid1-depleted cells as further down-regulation of NEUROSCIENCE PP2Ac rescued the axonal phenotype. Together, these data demon- Results strate that Mid1-dependent PP2Ac turnover is important for normal Mid1 Is Expressed in the Developing Brain and Enriched in the Axonal axonal development and that dysregulation of this process may Segment of Developing Neurons. Real-time PCR showed that Mid1 contribute to the underlying cause of OS. mRNA was strongly expressed, and at similar levels from em- bryonic day (E) 14 to adult in the mouse cerebral cortex (Fig. S1A). Similarly, the level of Mid1 protein remained relatively pitz G/BBB syndrome (OS) is a genetically heterogeneous high throughout development and peaked between E15 and disorder characterized by distinctive facial and genital fea- O postnatal day (P) 3, and then slightly decreased at later postnatal tures, as well as a spectrum of variably penetrant phenotypes, stages (Fig. S1B). In situ hybridization demonstrated that Mid1 including structural heart defects, structural brain anomalies, mRNA was abundant in the ventricular/subventricular zone intellectual disability, and developmental delay (1). The gene fi (VZ/SVZ) at E15 and extended to the cortical plate (CP) at E18 responsible for the X-linked form of OS has been identi ed and (Fig. 1A and Fig. S1C). After birth, Mid1 mRNA was primarily named Midline-1(MID1) (2). Mid1 encodes a 667-amino acid protein of the RBCC/TRIM family and has been shown to ex- Significance hibit E3 ligase activity (3). The Mid1 protein is highly conserved between rodents and human (4), and its transcript is expressed The gene responsible for the X-linked form of Opitz syndrome ubiquitously in embryonic tissues, with the highest levels ob- Midline-1 MID1 served in the progenitor cells of the central nervous system and (OS), ( ), encodes an E3 ubiquitin ligase and was where cell proliferation is active (4, 5). Full-length Mid1 protein reported to guide the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). But whether and how it is is associated with microtubules (6, 7), and the most frequently involved in neural development is unclear. We demonstrate reported cases of mutations in Mid1 occur at its C terminus (8), here that Mid1-dependent PP2Ac turnover is involved in axon which is known to disrupt its association with microtubules, leading development. Knocking down or knocking out Mid1 not only to the clustering of truncated Mid1 (6). Additional researches have promotes axon growth and branching in vitro, but also accel- implicated Mid1 in the development of Caenorhabditis elegans (9, erates axon elongation and disrupts the pattern of callosal 10), Xenopus (11), and chicken (12). However, whether and how projection in mouse cortex. These defects can be reversed by Mid1 plays a role in the development of the mammalian central down-regulating the accumulated PP2Ac in Mid1-depleted cells. nervous system, and especially in neuronal development, remains Dysfunction of this Mid1–PP2Ac pathway may underlie neural largely unknown. symptoms of OS patients. Previous studies revealed that Mid1 has multiple binding – α partners (13 15), including the 4 subunit of the major cellular Author contributions: T.L., R.C., and Z.X. designed research; T.L., R.C., R.X.M., N.K., G.T., L.X., phosphatase protein phosphatase 2A (PP2A). It guides the degra- J.Z., B.L., M.W., Q.S., and Y.L. performed research; T.C.C., J.K.P., and A.A. contributed new dation of the catalytic subunit in the PP2A complex (PP2Ac) reagents/analytic tools; T.L., R.C., and Q.S. analyzed data; and T.L., R.C., P.F.B., Q.S., L.J.R., (13). Recently, the Mid1–PP2Ac complex has been shown to be and Z.X. wrote the paper. involved in asthma (16) and in regulating mRNA translation The authors declare no conflict of interest. (17). Here, we report that Mid1-dependent turnover of PP2Ac is This article is a PNAS Direct Submission. required for proper axonal development, specifically for the 1T.L. and R.C. contributed equally to this work. control of axonal growth speed and branch formation. We 2To whom correspondence may be addressed. E-mail: [email protected] or xiongzhiqi@ reported that Mid1 is highly expressed in the cerebral cortex ion.ac.cn. during development and enriched in the axon segment of de- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. veloping neurons. Silencing Mid1 in cultured neurons increased 1073/pnas.1303687110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1303687110 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 the axon length and branch number were restored to control levels, demonstrating the specificity of the Mid1 RNAi construct (Fig. 2 A and B). In contrast, the dendritic morphology showed little difference among the three groups (Fig. S2D). To examine whether the axonal phenotype in Mid1–down-regulated neurons was observed only in cortical neurons, we repeated the above experiment in cultured hippocampal neurons. In a similar man- ner, knocking down Mid1 resulted in increased axonal growth and branching whereas cotransfecting Mid1 rescued this effect (Fig. S2E). To further dissect how Mid1 affects axon growth, time-lapse imaging was carried out in cultured neurons. We found that knocking down Mid1 promoted axon elongation whereas coex- pressing rMid1 restored this phenotype (Fig. 2C and Fig. S2G). By measuring the change of neurite length and branch number over 180 min, we showed that down-regulating Mid1 increased the speed of axonal growth and the rate of axon branching, without affecting dendrites (Fig. 2D and Fig. S2H). Furthermore, Fig. 1. Mid1 is expressed in the developing cortex and enriched in axons. replenishing rMid1 restored the growth speed and branching rate (A) Expression of Mid1 mRNA in the developing mouse cortex. CP, cortical of axons to control levels (Fig. 2D). plate; I-VI, cortical layer I-VI; IZ, intermediate zone; SVZ, subventricular zone; VZ, ventricular zone; WM, white matter. (B) Mid1 is associated with micro- tubules and mainly located in axons. Double staining of Mid1 and the in- Silencing Mid1 Accelerates Callosal Axon Growth and Branching. To dicated markers was performed in polarized neurons at 3 d in vitro (DIV). (C) determine the role of Mid1 during neuronal development in Mid1 is associated with tubulin in neurons. Coimmunoprecipitation was vivo, we electroporated the Mid1 RNAi and GFP into a sub- performed on lysate from cultured cortical neurons at 4 DIV with tubulin population of neural progenitor cells at E15 and analyzed brain antibody. Mouse IgG was used as control. Mid1 and tubulin were detected slices at different developmental stages. First, we sorted the with specific antibodies. (D) Mid1 is enriched in the axon segment. GFP- GFP-positive cells from electroporated mouse brains at P0 by transfected neurons were stained for Mid1 at 3 DIV. Relative immunofluo- fluorescent activated cell sorting (FACS). Both the GFP-positive rescence intensity of Mid1 in axons and dendrites was quantified. The ratio and GFP-negative cells were subjected to Western blotting of the intensity of Mid1 to GFP in dendrites was taken as 1. Results are in control and Mid1 RNAi animals. The result showed that shown as mean ± SEM. Fourteen neurons were analyzed. ***P < 0.001. Student t test. (Scale bars: A, 200 μm; B and D,20μm.) located in the cerebral cortex, olfactory bulb, hippocampus, and cerebellum (Fig.
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