RT Journal Article
SR Electronic
T1 Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) Regulates Retinal Axonal Projections by Inhibiting Eph and Abl Kinases in Mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 0128-18
DO 10.1523/JNEUROSCI.0128-18.2018
A1 Yang Yu
A1 Takafumi Shintani
A1 Yasushi Takeuchi
A1 Takuji Shirasawa
A1 Masaharu Noda
YR 2018
UL http://www.jneurosci.org/content/early/2018/08/06/JNEUROSCI.0128-18.2018.abstract
AB Eph receptors play pivotal roles in the axon guidance of retinal ganglion cells (RGCs) at the optic chiasm and the establishment of the topographic retinocollicular map. We previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) is specifically involved in the control of retinotectal projections in chicks through the dephosphorylation of EphA and EphB receptors. We subsequently revealed that all the mouse R3 subfamily members (PTPRB, PTPRH, PTPRJ, and PTPRO) of the receptor protein tyrosine phosphatase (RPTP) family inhibited Eph receptors as their substrates in cultured mammalian cells. We herein investigated the functional roles of R3 RPTPs in the projection of mouse retinal axon of both sexes. Ptpro and Ptprj were expressed in mouse RGCs; however, Ptprj expression levels were markedly higher than those of Ptpro. Consistent with their expression levels, Eph receptor activity was significantly enhanced in Ptprj-knockout (Ptprj-KO) retinas. In Ptprj-KO and Ptprj/Ptpro-double-KO (DKO) mice, the number of retinal axons that projected ipsilaterally or to the contralateral eye was significantly increased. Furthermore, retinal axons in Ptprj-KO and DKO mice formed anteriorly-shifted ectopic terminal zones in the superior colliculus. We found that c-Abl was downstream of ephrin-Eph signaling for the repulsion of retinal axons at the optic chiasm and in the superior colliculus. c-Abl was identified as a novel substrate for PTPRJ and PTPRO, and the phosphorylation of c-Abl was up-regulated in Ptprj-KO and DKO retinas. Thus, PTPRJ regulates retinocollicular projections in mice by controlling the activity of Eph and c-Abl kinases.Significance StatementCorrect retinocollicular projection is a prerequisite for proper vision. Eph receptors have been implicated in retinal axon guidance at the optic chiasm and the establishment of the topographic retinocollicular map. We herein demonstrated that PTPRJ regulated retinal axonal projections by controlling Eph activities. The retinas of Ptprj-KO and Ptpro/Ptprj double-KO mice exhibited significantly enhanced Eph activities over those in wild-type mice, and their axons showed defects in pathfinding at the chiasm and retinocollicular topographic map formation. We also revealed that c-Abl downstream of Eph receptors was regulated by PTPRJ. These results indicate that the regulation of the ephrin-Eph-c-Abl axis by PTPRJ plays pivotal roles in the proper central projection of retinal axons during development.