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PTEN deletion enhances the regenerative ability of adult corticospinal neurons

Abstract

Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

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Figure 1: Correlation between age-dependent decrease of CST sprouting and phospho-S6 levels in corticospinal neurons.
Figure 2: Pten deletion prevents p-S6 downregulation in corticospinal neurons after pyramidotomy.
Figure 3: Pten deletion promotes CST sprouting in adult mice with unilateral pyramidotomy.
Figure 4: Increased CST regrowth in Pten-deleted mice after T8 dorsal hemisection.
Figure 5: CST regeneration in PTEN deleted mice after a T8 spinal cord crush injury.
Figure 6: CST regeneration in PtenloxP/loxP mice with AAV injection at 4 weeks and T8 spinal cord crush injury at 8 weeks.
Figure 7: Regenerating CST axons after Pten deletion form synapse-structures in spinal segments caudal to a crush injury.

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Acknowledgements

We thank F. Wang for providing Rosa-stop-PLAP mice and M. Greenberg, M. Tessier-Lavigne and C. Woolf for reading the manuscript. This work was supported by grants from Wings for Life (K.L. and Z.H.), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Z.H.), the Craig H. Neilson Foundation (Y.L. and K.K.P.), the National Institute of Neurological Disorders and Stroke (Z.H., B.Z. and O.S.), the International Spinal Research Trust (Z.H.) and a private contribution to the Reeve-Irvine Research Center (O.S.). R.W. is the recipient of a predoctoral fellowship from the National Institute of Neurological Disorders and Stroke.

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K.L., Y.L., J.K.L., R.S., R.W., I.S.-K., A.T., K.K.P., D.J., B.C., B.X., L.C. and O.S. performed the experiments and analyzed the data. K.L., J.K.L., O.S., B.Z. and Z.H. drafted and edited the manuscript.

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Correspondence to Zhigang He.

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O.S. and Z.H. are co-founders of Axonis.

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Liu, K., Lu, Y., Lee, J. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 13, 1075–1081 (2010). https://doi.org/10.1038/nn.2603

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