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Novel Neurotrophic Factors

Heparin – Binding Growth Factors

Heparin – binding growth factors have been implicated in central nervous system development, regeneration and pathology. Typical members of this family of secreted cytokines are basic Fibroblast Growth Factor (human FGF-basic), Midkine and Pleiotrophin.

human Midkine, a 13 kDa heparin-binding growth factor with 50% sequence identity to Pleiotrophin is the product of a retinoic acid responsive gene and is a developmental regulated, highly conserved, neurotrophic factor2 which induces neurite extension3,4 and neuronal survival5. human Pleiotrophin, an 18 kDa, heparin–binding growth – associated molecule (HB-GAM,HBGF-8)6 is also a developmentally regulated neurotrophin which promotes neurite out growth7,8, axonal guidance9 and synaptogenesis6. Both factors are highly basic, lysine and cysteine rich which are produced in a recombinant form in E. coli10.

In vivo activities of these neurotrophic cytokines are cell surface and extracellular matrix-associated, promoting axonal growth, guidance, attachment and stabilization11. Most probably these neurotrophic cytokines employ different cell-specific receptors which upon occupancy, activate multiple signal transduction pathways. Midkine and Pleiotrophin have been found to bind to the receptor protein-tyrosine phosphatase zeta (PTP zeta)12, LDL receptor-related protein13, p200 (+) MKR cell surface receptor14, sulfatide15 and heparane-sulfate proteoglycans such as agrin16, N-syndecan9, ryudocan17 and neurocan12. They stimulate tyrosine phosphorylation18, mitogen activated protein kinases (MAPKS), and phosphoinositide 3-kinase pathways5.

human Persephin is a novel neurotrophic factor with 40% homology to human GDNF. Persephin, like GDNF, promotes the survival of mesencephalic dopaminergic and motor neurons in vitro19,20. Recombinant Persephin is a homodimeric 20.6 kDa protein consisting of two identical, 96 amino acid subunits. Persephin binds with high affinity to GFRα putative family of receptors21 which induces RET phosphorylation22.


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