title: Smad proteins differentially regulate transforming growth factor-β-mediated induction of chondroitin sulfate proteoglycans.
abstract: Traumatic injury to the CNS results in increased expression and deposition of chondroitin sulfate proteoglycans (CSPGs) that are inhibitory to axonal regeneration. Transforming growth factor-β (TGF-β) has been implicated as a major mediator of these changes, but the mechanisms through which TGF-β regulates CSPG expression are not known. Using lentiviral expressed Smad-specific ShRNA we show that TGF-β induction of CSPG expression in astrocytes is Smad-dependent. However, we find a differential dependence of the synthetic machinery on Smad2 and/or Smad3. TGF-β induction of neurocan and xylosyl transferase 1 required both Smad2 and Smad3, whereas induction of phosphacan and chondroitin synthase 1 required Smad2 but not Smad3. Smad3 knockdown selectively reduced induction of chondroitin-4-sulfotransferase 1 and the amount of 4-sulfated CSPGs secreted by astrocytes. Additionally, Smad3 knockdown in astrocytes was more efficacious in promoting neurite outgrowth of neurons cultured on the TGF-β-treated astrocytes. Our data implicate TGF-β Smad3-mediated induction of 4-sulfation as a critical determinant of the permissiveness of astrocyte secreted CSPGs for axonal growth.
authors: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors: Bala T S
authors: BT
authors: Susarla
authors: Eric D
authors: ED
authors: Laing
authors: Panpan
authors: P
authors: Yu
authors: Yasuhiro
authors: Y
authors: Katagiri
authors: Herbert M
authors: HM
authors: Geller
authors: Aviva J
authors: AJ
authors: Symes
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006025:Glycosaminoglycans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D006025:Glycosaminoglycans; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051785:Smad Proteins; D016212:Transforming Growth Factor beta