PMID- 29391597 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20230813 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 8 IP - 1 DP - 2018 Feb 1 TI - IGFBPL1 Regulates Axon Growth through IGF-1-mediated Signaling Cascades. PG - 2054 LID - 10.1038/s41598-018-20463-5 [doi] LID - 2054 AB - Activation of axonal growth program is a critical step in successful optic nerve regeneration following injury. Yet the molecular mechanisms that orchestrate this developmental transition are not fully understood. Here we identified a novel regulator, insulin-like growth factor binding protein-like 1 (IGFBPL1), for the growth of retinal ganglion cell (RGC) axons. Expression of IGFBPL1 correlates with RGC axon growth in development, and acute knockdown of IGFBPL1 with shRNA or IGFBPL1 knockout in vivo impaired RGC axon growth. In contrast, administration of IGFBPL1 promoted axon growth. Moreover, IGFBPL1 bound to insulin-like growth factor 1 (IGF-1) and subsequently induced calcium signaling and mammalian target of rapamycin (mTOR) phosphorylation to stimulate axon elongation. Blockage of IGF-1 signaling abolished IGFBPL1-mediated axon growth, and vice versa, IGF-1 required the presence of IGFBPL1 to promote RGC axon growth. These data reveal a novel element in the control of RGC axon growth and suggest an unknown signaling loop in the regulation of the pleiotropic functions of IGF-1. They suggest new therapeutic target for promoting optic nerve and axon regeneration and repair of the central nervous system. FAU - Guo, Chenying AU - Guo C AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. FAU - Cho, Kin-Sang AU - Cho KS AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. FAU - Li, Yingqian AU - Li Y AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. FAU - Tchedre, Kissauo AU - Tchedre K AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. FAU - Antolik, Christian AU - Antolik C AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. FAU - Ma, Jie AU - Ma J AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. FAU - Chew, Justin AU - Chew J AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. AD - Pritzker School of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, 60637, USA. FAU - Utheim, Tor Paaske AU - Utheim TP AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. AD - Department of Medical Biochemistry, Oslo University Hospital, Kirkeveien 166, 0407, Oslo, Norway. FAU - Huang, Xizhong A AU - Huang XA AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. AD - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Inc., Cambridge, MA, 02138, USA. FAU - Yu, Honghua AU - Yu H AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. FAU - Malik, Muhammad Taimur A AU - Malik MTA AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. FAU - Anzak, Nada AU - Anzak N AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. AD - Guys, Kings & St Thomas' School of Medicine, Hodgkin Building, Guy's Campus, King's College London, London, UK. FAU - Chen, Dong Feng AU - Chen DF AD - Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. dongfeng_chen@meei.harvard.edu. AD - Boston VA Healthcare System, 150 S. Huntington Ave, Boston, MA, 02130, USA. dongfeng_chen@meei.harvard.edu. LA - eng GR - R01 EY012983/EY/NEI NIH HHS/United States GR - R01 EY025259/EY/NEI NIH HHS/United States GR - R21 EY027067/EY/NEI NIH HHS/United States GR - I01 RX000110/RX/RRD VA/United States GR - T32 EY007145/EY/NEI NIH HHS/United States GR - P30 EY003790/EY/NEI NIH HHS/United States GR - R01 EY017641/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180201 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (IGFBPL1 protein, human) RN - 0 (Insulin-Like Growth Factor Binding Proteins) RN - 0 (Tumor Suppressor Proteins) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - *Calcium Signaling MH - Cells, Cultured MH - Insulin-Like Growth Factor Binding Proteins/*genetics/metabolism MH - Insulin-Like Growth Factor I/metabolism MH - Mice MH - Mice, Inbred C57BL MH - *Neuronal Outgrowth MH - PC12 Cells MH - Protein Binding MH - Rats MH - Retinal Ganglion Cells/cytology/*metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - Tumor Suppressor Proteins/*genetics/metabolism PMC - PMC5794803 COIS- C.G., K.-S.C., C.A., and D.F.C. are co-inventors on a pending patent application. The other authors declare no significant competing financial, professional, or personal interests that might influence the performance or presentation of the work described in this manuscript. EDAT- 2018/02/03 06:00 MHDA- 2018/12/12 06:00 PMCR- 2018/02/01 CRDT- 2018/02/03 06:00 PHST- 2017/05/30 00:00 [received] PHST- 2018/01/19 00:00 [accepted] PHST- 2018/02/03 06:00 [entrez] PHST- 2018/02/03 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2018/02/01 00:00 [pmc-release] AID - 10.1038/s41598-018-20463-5 [pii] AID - 20463 [pii] AID - 10.1038/s41598-018-20463-5 [doi] PST - epublish SO - Sci Rep. 2018 Feb 1;8(1):2054. doi: 10.1038/s41598-018-20463-5.