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The Journal of Neuroscience, February 20, 2008, 28(8):1961-1969; doi:10.1523/JNEUROSCI.3061-07.2008

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Development/Plasticity/Repair
TGFβ-Smad2 Signaling Regulates the Cdh1-APC/SnoN Pathway of Axonal Morphogenesis

Judith Stegmüller, Mai Anh Huynh, Zengqiang Yuan, Yoshiyuki Konishi, and Azad Bonni

Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Azad Bonni, Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: azad_bonni{at}hms.harvard.edu

Axon growth is critical to the establishment of neuronal connectivity. The E3 ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC) and its substrate the transcriptional modulator SnoN form a cell-intrinsic pathway that orchestrates axonal morphogenesis in the mammalian brain. How the Cdh1-APC/SnoN pathway is controlled in the nervous system remained unknown. Here, we report that the TGFβ-regulated signaling protein Smad2 plays a key role in regulating the Cdh1-APC/SnoN pathway in neurons. We find that Smad2 is expressed in primary granule neurons of the developing rat cerebellar cortex. The Smad signaling pathway is basally activated in neurons. Endogenous Smad2 is phosphorylated, localized in the nucleus, and forms a physical complex with endogenous SnoN in granule neurons. Inhibition of Smad signaling by several distinct approaches, including genetic knock-down of Smad2, stimulates axonal growth. Biochemical evidence and genetic epistasis analyses reveal that Smad2 acts upstream of SnoN in a shared pathway with Cdh1-APC in the control of axonal growth. Remarkably, Smad2 knock-down also overrides the ability of adult rat myelin to inhibit axonal growth. Collectively, our findings define a novel function for Smad2 in regulation of the Cdh1-APC/SnoN cell-intrinsic pathway of axonal morphogenesis, and suggest that inhibition of Smad signaling may hold therapeutic potential in stimulating axonal growth after injury in the CNS.

Key words: cerebellum; axon growth; Smad2; SnoN; Cdh1-APC; myelin; SB431542

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Received July 5, 2007; revised Dec. 31, 2007; accepted Jan. 2, 2008.

Correspondence should be addressed to Azad Bonni, Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: azad_bonni{at}hms.harvard.edu

This article has been cited by other articles:

				K. P. Sarker, H. Kataoka, A. Chan, S. J. Netherton, I. Pot, M. A. Huynh, X. Feng, A. Bonni, K. Riabowol, and S. Bonni ING2 as a Novel Mediator of Transforming Growth Factor-{beta}-dependent Responses in Epithelial Cells J. Biol. Chem., May 9, 2008; 283(19): 13269 - 13279. [Abstract] [Full Text] [PDF]

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