PTEN deletion enhances the regenerative ability of adult corticospinal neurons.

F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
Nature Neuroscience (Impact Factor: 15.25). 09/2010; 13(9):1075-81. DOI: 10.1038/nn.2603
Source: PubMed

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.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The corticospinal system-with its direct spinal pathway, the corticospinal tract (CST) - is the primary system for controlling voluntary movement. Our approach to CST repair after injury in mature animals was informed by our finding that activity drives establishment of connections with spinal cord circuits during postnatal development. After incomplete injury in maturity, spared CST circuits sprout, and partially restore lost function. Our approach harnesses activity to augment this injury-dependent CST sprouting and to promote function. Lesion of the medullary pyramid unilaterally eliminates all CST axons from one hemisphere and allows examination of CST sprouting from the unaffected hemisphere. We discovered that 10 days of electrical stimulation of either the spared CST or motor cortex induces CST axon sprouting that partially reconstructs the lost CST. Stimulation also leads to sprouting of the cortical projection to the magnocellular red nucleus, where the rubrospinal tract originates. Coordinated outgrowth of the CST and cortical projections to the red nucleus could support partial re-establishment of motor systems connections to the denervated spinal motor circuits. Stimulation restores skilled motor function in our animal model. Lesioned animals have a persistent forelimb deficit contralateral to pyramidotomy in the horizontal ladder task. Rats that received motor cortex stimulation either after acute or chronic injury showed a significant functional improvement that brought error rate to pre-lesion control levels. Reversible inactivation of the stimulated motor cortex reinstated the impairment demonstrating the importance of the stimulated system to recovery. Motor cortex electrical stimulation is an effective approach to promote spouting of spared CST axons. By optimizing activity-dependent sprouting in animals, we could have an approach that can be translated to the human for evaluation with minimal delay.
    Frontiers in Integrative Neuroscience 01/2014; 8:51.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The scarring response after a penetrant central nervous system injury results from the interaction between invading leptominingeal/pericyte-derived fibroblasts and endogenous reactive astrocytes about the wound margin. Extracellular matrix and scar-derived axon growth inhibitory molecules fill the lesion site providing both a physical and chemical barrier to regenerating axons. Decorin, a small leucine-rich chondroitin-dermatan sulphate proteoglycan expressed by neurons and astrocytes in the central nervous system, is both anti-fibrotic and anti-inflammatory and attenuates the formation and partial dissolution of established and chronic scars. Here, we discuss the potential of using Decorin to antagonise scarring in the central nervous system.
    Neural Regeneration Research 09/2014; 9(18):1653-1656. · 0.14 Impact Factor
  • Neural Regeneration Research 02/2014; 9(3):229-31. · 0.14 Impact Factor

Full-text (2 Sources)

Available from
May 31, 2014