RRC ID 53884
Author Okada T, Keino-Masu K, Nagamine S, Kametani F, Ohto T, Hasegawa M, van Kuppevelt TH, Kunita S, Takahashi S, Masu M.
Title Desulfation of Heparan Sulfate by Sulf1 and Sulf2 Is Required for Corticospinal Tract Formation.
Journal Sci Rep
Abstract Heparan sulfate (HS) has been implicated in a wide range of cell signaling. Here we report a novel mechanism in which extracellular removal of 6-O-sulfate groups from HS by the endosulfatases, Sulf1 and Sulf2, is essential for axon guidance during development. In Sulf1/2 double knockout (DKO) mice, the corticospinal tract (CST) was dorsally displaced on the midbrain surface. In utero electroporation of Sulf1/2 into radial glial cells along the third ventricle, where Sulf1/2 mRNAs are normally expressed, rescued the CST defects in the DKO mice. Proteomic analysis and functional testing identified Slit2 as the key molecule associated with the DKO phenotype. In the DKO brain, 6-O-sulfated HS was increased, leading to abnormal accumulation of Slit2 protein on the pial surface of the cerebral peduncle and hypothalamus, which caused dorsal repulsion of CST axons. Our findings indicate that postbiosynthetic desulfation of HS by Sulfs controls CST axon guidance through fine-tuning of Slit2 presentation.
Volume 7(1)
Pages 13847
Published 2017-10-23
DOI 10.1038/s41598-017-14185-3
PII 10.1038/s41598-017-14185-3
PMID 29062064
PMC PMC5653861
MeSH Animals Axon Guidance* Heparitin Sulfate / chemistry* Heparitin Sulfate / metabolism Mice Mice, Inbred C57BL Mice, Knockout Phenotype Proteomics Pyramidal Tracts / metabolism Pyramidal Tracts / pathology* Signal Transduction Spinal Cord Injuries / metabolism Spinal Cord Injuries / pathology* Sulfatases / physiology* Sulfates / chemistry Sulfates / metabolism* Sulfotransferases / physiology*
IF 3.998
Times Cited 4
DNA material pCX-rSulf1-FLAG (RDB16018) pCX-rSulf2-Myc (RDB16019) pEF-BOS-rSulf1-FLAG (RDB16020) pEF-BOS-rSulf2-Myc (RDB16021) pCX-Kozak-SS-FLAG-His-rSulf1-Myc-His (RDB16022) pCX-Kozak-SS-FLAG-His-rSulf2-Myc (RDB16023) pCX-mSlit1 (RDB16024) pCX-mSlit2 (RDB16025) pCX-mSema3e (RDB16026) pCX-mSema4d (RDB16027) pCX-mSema4g (RDB16028) pCX-mSema5b (RDB16029) pCX-mSema6b (RDB16030) pCX-mEfnb2 (RDB16031) pEF-BOS-mSlit2 (RDB16032) pCX-rRobo2-Fc (RDB16033) pEF-BOS-mSlit1 (RDB16034) pMT21-rRobo2-Fc (RDB16035) pCEP4-FLAG-rSlit2 (RDB16036)