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Regeneration of Axons in Injured Spinal Cord by Activation of Bone Morphogenetic Protein/Smad1 Signaling Pathway in Adult Neuron

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Regeneration of Axons in Injured Spinal Cord by Activation of Bone Morphogenetic Protein/Smad1 Signaling Pathway in Adult Neuron Regeneration of axons in injured spinal cord by PNAS PLUS activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons Pranav Parikha,b,1, Yuhan Haoa,b,1, Mohsen Hosseinkhania,b, Shekhar B. Patila, George W. Huntleya, Marc Tessier-Lavignec, and Hongyan Zoua,b,2 aFishberg Department of Neuroscience and bDepartment of Neurosurgery, Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029; and cGenentech, Inc., South San Francisco, CA 94080 Edited by Mark H. Tuszynski, University of California at San Diego, La Jolla, CA, and accepted by the Editorial Board April 1, 2011 (received for review January 11, 2011) Axon growth potential is highest in young neurons but diminishes to reactivate Smad1 contributes to a lack-of-growth state after SCI with age, thus becoming a significant obstacle to axonal regener- and whether empowering older neurons with increased Smad1 ation after injury in maturity. The mechanism for the decline is signaling can promote axon regeneration after SCI in vivo. Here we incompletely understood, and no effective clinical treatment is show that Smad1-dependent BMP signaling is developmentally available to rekindle innate growth capability. Here, we show that regulated and governs axon growth potential and that activating Smad1-dependent bone morphogenetic protein (BMP) signaling is Smad1 in adult DRG neurons by adeno-associated virus (AAV)- developmentally regulated and governs axonal growth in dorsal BMP enhances regrowth of adult sensory axons in vivo. root ganglion (DRG) neurons. Down-regulation of the pathway Results contributes to the age-related decline of the axon growth poten- tial. Reactivating Smad1 selectively in adult DRG neurons results in Smad1 Is Developmentally Regulated in DRG Neurons and Governs Axon Growth Potential. Smads are the intracellular mediators of sensory axon regeneration in a mouse model of spinal cord injury β β (SCI). Smad1 signaling can be effectively manipulated by an adeno- the TGF- /BMP signaling pathway. TGF- /BMP ligands activate associated virus (AAV) vector encoding BMP4 delivered by a clini- receptor serine/threonine kinases, which in turn signal through NEUROSCIENCE C-terminal phosphorylation of Smads, leading to nuclear trans- cally applicable and minimally invasive technique, an approach location of pSmads. Smad1, -5, and -8 mediate signaling of devoid of unwanted abnormalities in mechanosensation or pain members of the BMP subfamily (16). We first examined whether perception. Importantly, transected axons are able to regenerate Smad1 is expressed in embryonic DRG neurons during the pe- even when the AAV treatment is delivered after SCI, thus mimick- riod of active axon growth. In situ hybridization of embryonic ing a clinically relevant scenario. Together, our results identify a spinal cord showed that Smad1 was strongly expressed in the therapeutic target to promote axonal regeneration after SCI. embryonic day (E)12.5 spinal cord and DRGs (Fig. 1A). In contrast, Smad5 transcripts were mostly detected in the peri- intrinsic axon growth capacity | intrathecal viral vector delivery ventricular zone of the developing spinal cord, whereas Smad8 was expressed at low level in E12.5 DRGs (Fig. S1A). Thus, pinal cord injury (SCI) disrupts long-projection axons, with Smad1 seems to be the dominant Smad that mediates BMP sig- devastating neurological outcomes, yet no effective clinical naling in developing DRG neurons. We also examined Smad2, S β treatment exists. Neurons fail to regenerate axons because of a a mediator of the TGF- subfamily, and found less-abundant A growth-inhibiting environment at the injury site (1–4) and because expression level in E12.5 DRGs (Fig. S1 ). Smad1 of an age-dependent decline in the intrinsic axon growth potential We next conducted a time course analysis. started to be expressed in DRGs at E10.5 and persisted through E15.5 (Fig. (5, 6). Nevertheless, blocking extracellular inhibitory molecules B (7–10) or alleviating the intracellular negative regulators of axonal S1 ). Consistent with its role as a transcription factor, we found abundant phosphorylated Smad1 (pSmad1) in the nuclei of em- growth (5, 6, 11, 12) enables only limited axonal regeneration. Thus, E additional molecular pathways that can rekindle innate growth bryonic DRG neurons by immunohistochemistry (Fig. 1 and Fig. fi S1C). In contrast, in adult DRG neurons, pSmad1 is down-regu- capability must exist but remain unidenti ed (13). F G Dorsal root ganglion (DRG) neurons are a favored model sys- lated (Fig. 1 ) but reappears after a conditioning lesion (Fig. 1 ) (15). The dynamic expression pattern of pSmad1 coincides tem to study axonal regeneration. These neurons have an axon with with the changes of the intrinsic axon growth potential: em- two branches—a peripheral branch that innervates sensory organs bryonic and conditioned adult DRG neurons were able to ex- and a central branch that relays information to the CNS. The tend much longer axons than adult naïve neurons in dissociated central branches of adult DRG neurons in the spinal cord are re- cultures (Fig. 1 B–D and H). pSmad1 was also found in the fractory to regeneration unless their peripheral branches are sev- fi “ ” nuclei of motor neurons in the developing spinal cord and facial ered rst. This so-called conditioning lesion paradigm activates nucleus, as wells as in Purkinje, retinal ganglionic, and olfactory a transcription program that enhances the intrinsic axonal growth potential (14). Previously, through gene expression profiling, we have demonstrated that Smad1 is induced after peripheral axotomy and that intraganglionic delivery of bone morphogenetic protein 2 Author contributions: H.Z. designed research; P.P., Y.H., M.H., S.B.P., and H.Z. performed or 4 (BMP2 or -4) activates Smad1 and enhances the axon growth research; S.B.P., G.W.H., and M.T.-L. contributed new reagents/analytic tools; P.P., Y.H., potential of adult DRG neurons in cultures. In contrast, severing M.H., G.W.H., and H.Z. analyzed data; and G.W.H., M.T.-L., and H.Z. wrote the paper. the central branches of DRGs fails to activate the Smad1 pathway, The authors declare no conflict of interest. which correlates with the absence of regeneration after SCI (15). This article is a PNAS Direct Submission. M.H.T. is a guest editor invited by the Editorial These results suggested a possible involvement of Smad1 in Board. regulating the growth state of DRG neurons. It is not known, 1P.P. and Y.H. contributed equally to this work. however, whether Smad1 governs the axon growth program in 2To whom correspondence should be addressed. E-mail: [email protected]. young neurons and whether down-regulation of this pathway See Author Summary on page 7661. underlies the age-related decline of the intrinsic axon growth po- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tential. Furthermore, it remains to be determined whether failure 1073/pnas.1100426108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1100426108 PNAS | May 10, 2011 | vol. 108 | no. 19 | E99–E107 Downloaded by guest on October 6, 2021 A B C D EF G H I J KL MN O P Q Fig. 1. Smad1 is developmentally regulated and critical for axonogenesis. (A) In situ hybridization of embryonic spinal cord at day 12.5 demonstrating that Smad1 is strongly expressed in DRGs (outlined in dashed lines). (B–H) E12.5 DRG neurons (B) and conditioned adult DRG neurons (D) extended much longer axons than adult naive counterparts (C) in culture assay at 1 d in vitro. Quantification in H. Immunostaining showed that pSmad1 is developmentally reg- ulated: high in E12.5 DRG (E), low in adult DRG (F), and reactivated by a conditioning lesion in adult mice (G). Tuj1: green, pSmad1: red. (I–L) Neurite outgrowth of E12.5 DRG neurons in explants (I and J) or dissociated cultures (K and L) was inhibited by DM in a dose-dependent manner. Growth cones were dystrophic compared with controls (arrows). Culture media contained 12.5 ng/mL NGF. (M and N) Smad1 siRNA-mediated knockdown of Smad1 in E12.5 DRG significantly impaired axonal growth compared with control siRNA. This could be rescued by an RNAi-resistant Smad1 plasmid. (N) Quantification of the average of the longest axon. (O–Q) In dissociated neuronal cultures of E12.5 DRG grown on fibronectin, at 1 d in vitro, axon-bearing neurons (arrow) all had nuclear pSmad1 (red), whereas neurons that had not extended axons did not. BMP7 (2 μg/mL) increased the pSmad1 in the nuclei (O), axonal length (Q), and the percentage of axon-bearing neurons (P). Tuj1 stains entire neurons. *P < 0.05, ***P < 0.0001; one-way ANOVA followed by Bonferroni’s post hoc test. (Scale bars, 25 μminK, Lower, and O;50μminM; 100 μminB–G and K, Upper; and 500 μminA and I.) mitral cells (Fig. S1 C–G), suggesting that it might also be in- we took advantage of a selective small-molecule inhibitor of type volved in axonogenesis of other classes of neurons. I BMP receptor kinases, dorsomorphin (DM) (17). In E12.5 To test the model that a high level of BMP/Smad1 signaling DRG explant cultures, DM strongly inhibited axon growth in contributes to the robust growth potential in embryonic neurons, a dose-dependent fashion (Fig. 1 I and J). The effect seemed to E100 | www.pnas.org/cgi/doi/10.1073/pnas.1100426108 Parikh et al. Downloaded by guest on October 6, 2021 be cell autonomous: neurons in low-density dissociated cultures (Fig. 3A). Intrathecal AAV-GFP injection led to high and se- PNAS PLUS showed a similar dose-dependent inhibition (Figs. 1 K and L). lective transduction of DRG neurons (up to 50% in lumbosacral, When BMP signaling was blocked, growth-associated protein 43 12% in thoracic, and 30% in cervical DRGs) (Fig.
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