Mi, R., Chen, W., and Hoke, A. Pleiotrophin is a neurotrophic factor for spinal motor neurons. Proc. Nat. Acad. Sci., 104 (11), 4664-4669 (March 13, 2007).
A cDNA microarray was used to identify potential neurotrophic factors in denervated distal nerve stumps. Pleiotrophin (PTN) mRNA levels increase significantly in Schwann cells within two days after sciatic nerve transaction and remain elevated for at least a month. However, by the third month, PTN mRNA returns to baseline.
An analysis of PTN expression during development suggests that this 168 amino acid protein plays a role in normal embryogenesis. At embryonic day 14, PTN mRNA is roughly 11,000 times higher than in the adult rat tibialis anterior muscle. Following birth, the mRNA declines, reaching an adult level by postnatal day 30.
Addition of PTN or PTN expressing HEK-293 cells to cultures of spinal cord motor neurons enhances axonal growth and protects the neurons from excitotoxic effects of the glutamate transport inhibitor threohydroxyaspartate. Similar results were observed in vivo, following sciatic nerve transaction when PTN-expressing HEK-293 cells were included in a silicone tube used for supporting axon regeneration. The presence of PTN increases the number of regenerated myelinated axons, compared with control animals, and it leads to the reemergence of compound motor action potentials in sciatic nerve innervated foot muscles. PTNís neuroprotective properties were investigated in vivo by transecting the facial nerve in neonatal mice. Implants of HEK-293 cells that express the neurotrophic factor rescue the facial motor neurons.
A semiquantitative real-time RT-PCR analysis was used to identify which receptors were increased in response to axotomy. The results revealed that of the four possible PTN receptors, only anaplastic lymphoma kinase (ALK) is upregulated. Moreover, an antibody to ALK was able to block both the axonal regeneration and neuroprotective properties of PTN in cell cultures, indicating that ALK serves a crucial role in the PTN pathway.
The results open a new approach to a therapy that stimulates motor neuron regeneration clinically.
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