Axotomy-induced Smad1 activation promotes axonal growth in adult sensory neurons.
Mature neurons have diminished intrinsic regenerative capacity. Axotomy of the peripheral branch of adult dorsal root ganglia (a "conditioning" lesion) triggers a transcription-dependent axon growth program. Here, we show that this growth program requires the function of the transcription factor Smad1. After peripheral axotomy, neuronal Smad1 is upregulated, and phosphorylated Smad1 accumulates in the nucleus. Both events precede the onset of axonal extension. Reducing Smad1 by RNA interference in vitro impairs axonal growth, and the continued presence of Smad1 is required to maintain the growth program. Furthermore, intraganglionic injection of BMP2 or 4, which activates Smad1, markedly enhances axonal growth capacity, mimicking the effect of a conditioning lesion. Thus, activation of Smad1 by axotomy is a key component of the transcriptional switch that promotes an enhanced growth state of adult sensory neurons.
Zou
Hongyan
H
Genentech, Inc., South San Francisco, California 94080, USA.
Ho
Carole
C
Wong
Karen
K
Tessier-Lavigne
Marc
M
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D019771:Axotomy / Q000379:methods; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000166:cytology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D046228:Microarray Analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D011984:Sensory Receptor Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D034741:RNA, Small Interfering; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D014404:Tubulin; C462941:beta3 tubulin, mouse