Abstract
Reorganization of spared neural network connections is one of the most important processes for restoring impaired function after brain injury. However, plasticity is quite limited in the adult brain due to the presence of inhibitory molecules and a lack of intrinsic neuronal signals for axonal growth. Src homology 2-containing phosphatase (SHP)-1 has been shown to have a role in axon growth inhibition. Here, we tested the hypothesis that SHP-1 negatively affects axonal reorganization. We observed that unilateral motor cortex injury led to increased expression and activity of SHP-1 in the contralesional cortex. In this model, corticospinal axons originating from the contralesional cortex sprouted into the denervated side of the cervical spinal cord after injury. We observed that the number of sprouting fibers was increased in SHP-1-deficient heterozygous viable motheaten (+/mev) mice, which show reduced SHP-1 activity, and in wild-type mice treated with an SHP inhibitor. Motor function recovery of impaired forelimb was enhanced in +/mev mice. Collectively, our results indicate that downregulation of SHP-1 activity promotes corticospinal tract sprouting and functional recovery after brain injury.
Highlights
Function is not completely recovered due to the lack of ability to regenerate or reorganize adult central nervous system (CNS) axons
We asked whether downregulation of Src homology 2-containing phosphatase-1 (SHP-1) activity enhances corticospinal tract (CST) sprouting and functional recovery after unilateral cortical injury in SHP-1deficient heterozygous viable motheaten ( þ /mev) mice or in wild-type ( þ / þ ) mice treated with a SHP inhibitor
The current study examined the role of SHP-1 on CST sprouting from the contralesional motor cortex, which is thought to contribute to motor function recovery.[3,15,16,17,18,19]
Summary
Function is not completely recovered due to the lack of ability to regenerate or reorganize adult central nervous system (CNS) axons. Myelin-derived proteins, such as myelinassociated glycoprotein (MAG), Nogo and oligodendrocyte myelin glycoprotein (OMgp) potently inhibit axonal plasticity.[4,5] these proteins are structurally distinct, they all bind to the Nogo receptor and paired immunoglobulin-like receptor B (PIR-B), which transduce signals that inhibit axon growth.[6,7] PIR-B recruits Src homology 2-containing phosphatase-1 (SHP-1), an intracellular cytoplasmic protein tyrosine phosphatase (PTP).[8,9,10] SHP-1, a member of the SHP family of PTPs, is recruited to PIR-B upon MAG stimulation and is required for MAG-induced neurite growth inhibition and dephosphorylation of tropomyosin receptor kinase B (TrkB).[11] TrkB encodes a receptor for brain-derived neurotrophic factor (BDNF),[12,13] and BDNF/TrkB signaling is important for axonal regeneration and rewiring.[14,15] We previously demonstrated that inhibition of SHP-1 signaling enhanced axonal regeneration after optic nerve injury.[11] These studies suggest that SHP-1 is a key signaling molecule that mediates axonal growth inhibition via myelin-dependent signals and inactivation of growth factor signaling. The current study examined the role of SHP-1 on CST sprouting from the contralesional motor cortex, which is thought to contribute to motor function recovery.[3,15,16,17,18,19]
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