Secreted Sulfatases Sulf1 and Sulf2 Have Overlapping yet Essential Roles in Mouse Neonatal Survival 英文参考文献.docVIP

SecretedSulfatasesSulf1andSulf2HaveOverlapping yetEssentialRolesinMouseNeonatalSurvival CharlesR.Holst1,HaniBou-Reslan2,BryanB.Gore3,6,KarenWong3,DeannaGrant4,SreedeviChalasani5,RichardA.Carano2,GretchenD. Frantz5,MarcTessier-Lavigne3,BradBolon7,DorothyM.French5,AviAshkenazi1* 1Department of Molecular Oncology, Genentech, Inc., South San Francisco, California, United States of America, 2Department of Biomedical Imaging,Genentech,Inc.,SouthSanFrancisco,California,UnitedStatesofAmerica,3DepartmentofResearchDrugDiscovery,Genentech,Inc.,South SanFrancisco,California,UnitedStatesofAmerica,4DepartmentofMolecularBiology,Genentech,Inc.,SouthSanFrancisco,California,UnitedStates of America, 5Department of Pathology, Genentech, Inc., South San Francisco, California, United States of America, 6Graduate Program in Neurosciences,StanfordUniversity,Stanford,California,UnitedStatesofAmerica,7GEMpath,Inc.,CedarCity,Utah,UnitedStatesofAmerica Background.Heparansulfateproteoglycans(HSPGs)usehighlysulfatedpolysaccharideside-chainstointeractwithseveral key growth factors and morphogens, thereby regulating their accessibility and biological activity. Various sulfotransferases and sulfatases with differing specificities control the pattern of HSPG sulfation, which is functionally critical. Among these enzymesinthemousearetwosecreted6-O-endosulfatases,Sulf1andSulf2,whichmodifyHSPGsintheextracellularmatrix andonthecellsurface.TherolesofSulf1andSulf2duringnormaldevelopmentarenotwellunderstood.Methods/Results. ToinvestigatetheimportanceofSulf1andSulf2forembryonicdevelopment,wegeneratedmicegeneticallydeficientinthese genes and assessed the phenotypes of the resulting secreted sulfatase-deficient mice. Surprisingly, despite the established crucial role of HSPG interactions during development, neither Sulf1- nor Sulf2-deficient mice showed significant developmental flaws. In contrast, mice deficient in both Sulf1and Sulf2 exhibited highly penetrant neonatal lethality. Loss ofviabilitywasass