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Chapter 36,197

Smad proteins differentially regulate TGF-? mediated induction of chondroitin sulfate proteoglycans


2011


DOI: 10.1111/j.1471-4159.2011.07470.x
Accession: 036196277

Traumatic injury to the central nervous system results in increased expression and deposition of chondroitin sulfate proteoglycans (CSPGs) that are inhibitory to axonal regeneration. Transforming growth factor ? (TGF-?) has been implicated as a major mediator of these changes, but the mechanisms through which TGF-? regulates CSPG expression are not known. Using lentiviral expressed Smad-specific shRNA we show that TGF-? 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-? 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-? treated astrocytes. Our data implicate TGF-? -Smad3 mediated induction of 4-sulfation as a critical determinant of the permissiveness of astrocyte secreted CSPGs for axonal growth.

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