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MND impair the Ran GTPase cycle, which controls nucleocytoplasmic transport, ribostasis and proteostasis; however, cause-effect mechanisms of Ran GTPase modulators in motoneuron pathobiology are heretofore elusive. The cytosolic and peripheral nucleoporin, Ranbp2, is a critical regulator of the Ran GTPase cycle and proteostasis of neurological disease-prone substrates, but the roles of Ranbp2 in motoneuron biology and disease remain unknown. This study shows that conditional ablation of Ranbp2 in mouse Thy1-motoneurons causes ALS syndromes with hypoactivity followed by hind limb paralysis, respiratory distress and ultimately, death. These phenotypes are accompanied by declines of nerve conduction velocity, free fatty acids and phophatidylcholine of the sciatic nerve, g-ratios of sciatic and phrenic nerves, and hypertrophy of motoneurons. Further, Ranbp2 loss disrupts the nucleocytoplasmic partitioning of the import and export nuclear receptors, importin-\u03b2 and exportin-1, respectively, Ran GTPase and histone deacetylase-4. Whole-transcriptome, proteomic and cellular analyses uncovered that the chemokine receptor, Cxcr4, its antagonizing ligands, Cxcl12 and Cxcl14, and effector, latent and activated Stat3, undergo early autocrine and proteostatic deregulation, and intracellular sequestration and aggregation, by Ranbp2 loss in motoneurons. These effects were accompanied by paracrine and autocrine neuroglial deregulation of hnRNPH3 proteostasis in sciatic nerve and motoneurons, respectively, and post-transcriptional down-regulation of metalloproteinase-28 in the sciatic nerve. Mechanistically, our results demonstrate that Ranbp2 controls nucleocytoplasmic, chemokine and metalloproteinase-28 signaling and proteostasis of substrates critical to motoneuronal homeostasis and whose impairments by loss of Ranbp2 drive ALS-like syndromes.<\/jats:p>","DOI":"10.1242\/dmm.027730","type":"journal-article","created":{"date-parts":[[2017,1,19]],"date-time":"2017-01-19T02:10:54Z","timestamp":1484791854000},"source":"Crossref","is-referenced-by-count":29,"title":["Loss of Ranbp2 in motor neurons causes the disruption of nucleocytoplasmic and chemokine signaling and proteostasis of hnRNPH3 and Mmp28, and the development of amyotrophic lateral sclerosis (ALS)-like syndromes"],"prefix":"10.1242","author":[{"given":"Kyoung-in","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dosuk","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Danziger","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren M.","family":"Grill","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Wetsel","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4585-1717","authenticated-orcid":false,"given":"Paulo A.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Department of Pathology Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2017,1,1]]},"reference":[{"key":"2021042500131557000_DMM027730C1","doi-asserted-by":"publisher","first-page":"6692","DOI":"10.1074\/jbc.M408481200","article-title":"Identification of the cytoplasmic domains of CXCR4 involved in Jak2 and STAT3 phosphorylation","volume":"280","author":"Ahr","year":"2005","journal-title":"J. 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