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Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) Regulates Retinal Axonal Projections by Inhibiting Eph and Abl Kinases in Mice

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Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) Regulates Retinal Axonal Projections by Inhibiting Eph and Abl Kinases in Mice This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Development/Plasticity/Repair Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) Regulates Retinal Axonal Projections by Inhibiting Eph and Abl Kinases in Mice Yang Yu1,2, Takafumi Shintani1,2, Yasushi Takeuchi2, Takuji Shirasawa3 and Masaharu Noda1,2 1Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan 2School of Life Science, Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan 3Shirasawa Anti-Aging Medical Institute, Tokyo 113-0033, Japan DOI: 10.1523/JNEUROSCI.0128-18.2018 Received: 18 January 2018 Revised: 5 July 2018 Accepted: 30 July 2018 Published: 6 August 2018 Author contributions: Y.Y., T. Shintani, and Y.T. performed research; Y.Y. and T. Shintani analyzed data; Y.Y., T. Shintani, and M.N. wrote the first draft of the paper; T. Shintani and M.N. designed research; T. Shintani and M.N. edited the paper; T. Shintani and M.N. wrote the paper; T. Shirasawa contributed unpublished reagents/ analytic tools. Conflict of Interest: The authors declare no competing financial interests. We thank Drs. E. Gaudio, F. Trapasso, and A. Fusco for providing us with targeted Ptprj heterozygous mice. We thank the RIKEN BRC for providing us with targeted Ptpro heterozygous mice (T. Shirasawa generated the mouse line at the Tokyo Metropolitan Institute of Gerontology). We thank Ms. K. Wada and Y. Dokyo for their technical assistance, and Ms. A. Kodama for her secretarial assistance. We thank members of the Model Animal Research Facility of the National Institute for Basic Biology (NIBB) Bioresource Center for animal care. We thank the Functional Genomics Facility in the NIBB Core Research Facilities for their technical support. This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. N.). Correspondence should be addressed to: Masaharu Noda, Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan. E-mail: [email protected]; and Takafumi Shintani, Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan. E-mail: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.0128-18.2018 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 Journal Section: Development/Plasticity/Repair 2 Title: 3 Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) Regulates Retinal Axonal 4 Projections by Inhibiting Eph and Abl Kinases in Mice 5 Abbreviated title: Regulation of Retinal Projections by PTPRJ 6 Yang Yu1,2, Takafumi Shintani1,2, Yasushi Takeuchi2, Takuji Shirasawa3, and Masaharu Noda1,2 7 1Division of Molecular Neurobiology, National Institute for Basic Biology, 8 Okazaki 444-8787, Japan 9 2School of Life Science, Graduate University for Advanced Studies (SOKENDAI), 10 Okazaki 444-8787, Japan 11 3Shirasawa Anti-Aging Medical Institute, Tokyo 113-0033, Japan 12 Correspondence should be addressed to: Masaharu Noda, Division of Molecular 13 Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan. E-mail: 14 [email protected]; and Takafumi Shintani, Division of Molecular Neurobiology, National 15 Institute for Basic Biology, Okazaki 444-8787, Japan. E-mail: [email protected] 16 Number of pages, 17 Number of figures, 11 18 Number of tables, 0 19 Number of multimedia, 0 20 Number of 3D models, 0 21 Number of words for Abstract, 244; Introduction, 638; Discussion: 1279. 22 23 Author contributions: 24 T. Shintani and M.N. designed the research; Y.Y., T. Shintani and Y.T. performed the research; 25 Y.Y. and T. Shintani analyzed data; T. Shirasawa generated Ptpro-deficient mice; Y.Y., T. 26 Shintani, and M.N. wrote the manuscript. 27 28 The authors declare no competing financial interests. 29 30 Acknowledgments: We thank Drs. E. Gaudio, F. Trapasso, and A. Fusco for providing us with targeted Ptprj heterozygous mice. We thank the RIKEN BRC for providing us with targeted Ptpro heterozygous mice (T. Shirasawa generated the mouse line at the Tokyo Metropolitan Institute of Gerontology). We thank Ms. K. Wada and Y. Dokyo for their technical assistance, and Ms. A. Kodama for her secretarial assistance. We thank members of the Model Animal Research Facility of the National Institute for Basic Biology (NIBB) Bioresource Center for animal care. We thank the Functional Genomics Facility in the NIBB Core Research Facilities for their technical support. This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. N.). 2 31 Abstract 32 Eph receptors play pivotal roles in the axon guidance of retinal ganglion cells (RGCs) at the optic 33 chiasm and the establishment of the topographic retinocollicular map. We previously 34 demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) is specifically involved 35 in the control of retinotectal projections in chicks through the dephosphorylation of EphA and 36 EphB receptors. We subsequently revealed that all the mouse R3 subfamily members (PTPRB, 37 PTPRH, PTPRJ, and PTPRO) of the receptor protein tyrosine phosphatase (RPTP) family 38 inhibited Eph receptors as their substrates in cultured mammalian cells. We herein investigated 39 the functional roles of R3 RPTPs in the projection of mouse retinal axon of both sexes. Ptpro 40 and Ptprj were expressed in mouse RGCs; however, Ptprj expression levels were markedly higher 41 than those of Ptpro. Consistent with their expression levels, Eph receptor activity was 42 significantly enhanced in Ptprj-knockout (Ptprj-KO) retinas. In Ptprj-KO and 43 Ptprj/Ptpro-double-KO (DKO) mice, the number of retinal axons that projected ipsilaterally or to 44 the contralateral eye was significantly increased. Furthermore, retinal axons in Ptprj-KO and 45 DKO mice formed anteriorly-shifted ectopic terminal zones in the superior colliculus. We found 46 that c-Abl was downstream of ephrin-Eph signaling for the repulsion of retinal axons at the optic 47 chiasm and in the superior colliculus. c-Abl was identified as a novel substrate for PTPRJ and 48 PTPRO, and the phosphorylation of c-Abl was up-regulated in Ptprj-KO and DKO retinas. 49 Thus, PTPRJ regulates retinocollicular projections in mice by controlling the activity of Eph and 50 c-Abl kinases. 51 52 Key words: R3 RPTPs; PTPRJ; PTPRO; Eph receptors; topographic maps; c-Abl 3 53 Significance Statement 54 Correct retinocollicular projection is a prerequisite for proper vision. Eph receptors have been 55 implicated in retinal axon guidance at the optic chiasm and the establishment of the topographic 56 retinocollicular map. We herein demonstrated that PTPRJ regulated retinal axonal projections 57 by controlling Eph activities. The retinas of Ptprj-KO and Ptpro/Ptprj double-KO mice 58 exhibited significantly enhanced Eph activities over those in wild-type mice, and their axons 59 showed defects in pathfinding at the chiasm and retinocollicular topographic map formation. We 60 also revealed that c-Abl downstream of Eph receptors was regulated by PTPRJ. These results 61 indicate that the regulation of the ephrin-Eph-c-Abl axis by PTPRJ plays pivotal roles in the 62 proper central projection of retinal axons during development. 4 63 Introduction 64 The correct axonal projections of retinal ganglion cells (RGCs) are a prerequisite for proper vision 65 and vision-guided behaviors (Simon and O’Leary, 1992). In mammals, the optic chiasm is the 66 major midline choice point for retinal axons; some retinal axons avoid passing the midline and 67 project ipsilaterally, which is considered to be necessary for acquiring high-quality binocular 68 vision and stereopsis (Jeffery, 2001). In mice, only RGCs in the ventrotemporal (VT) crescent 69 project ipsilaterally, while RGCs from all other retinal regions project contralaterally (Fig. 1A). 70 A previous study reported that retinal axons from the VT portion specifically expressed high 71 levels of EphB1 receptors in order to sense ephrinB2 at the chiasm and turn ipsilaterally 72 (Williams et al., 2003). 73 Retinal axons establish a topographic map in the SC in order to generate a spatially matched 74 projection of visual images to the brain; nasal and temporal axons project to the posterior and 75 anterior SC, respectively, while dorsal and ventral retinas are connected to the lateral and medial 76 SC, respectively (Fig. 1B). The importance of ephrinA-EphA signaling in topographic map 77 formation along the anterial-posterial (A-P) axis of the SC has already been established (Brown et 78 al., 2000; Wilkinson, 2000; Takahashi et al., 2003; McLaughlin and O’Leary, 2005; Sakuta et al., 79 2006; Takahashi et al., 2009). In the mouse retina, EphAs are expressed in a decreasing gradient 80 from temporal to nasal axons, and ephrinAs from the posterior to anterior SC (Connor et al., 1998) 81 (Fig. 1B). EphrinA-EphA repellent interactions between the SC and retinal axons control 82 projections along the A-P axis: axons strongly expressing EphA are impeded from invading the 83 ephrinA-rich posterior part of the SC, while those weakly expressing EphA are permitted to enter 84 and terminate there (Marcus et al., 1996; Hornberger et al., 1999). 85 However, EphBs are expressed in a ventral high-dorsal low gradient, while ephrinBs are 86 expressed in a dorsal high-ventral low gradient in the retina of mice (McLaughlin et al., 2003a) 87 (Fig. 1B). In the SC, a medial high-lateral low gradient of ephrinB1 has been detected in mice 5 88 (Hindges et al., 2002). Therefore, the interactions between EphBs on ventral retinal axons and 89 ephrinBs in the medial SC are considered to be attractive, but not repulsive (McLaughlin et al., 90 2003b).
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