Winkler, C., and Yao, S. (2014) The midkine family of growth factors: Diverse roles in nervous system formation and maintenance. British journal of pharmacology. 171(4):905-12.
Midkines are heparin-binding growth factors implicated in a wide range of biological processes. Originally identified as retinoic acid inducible genes, midkines are widely expressed during embryogenesis with particularly high levels in the developing nervous system. During postnatal stages, midkine expression generally ceases but is often up-regulated under disease conditions most notably those affecting the nervous system. Midkines are known as neurotrophic factors, as they promote neurite outgrowth and neuron survival in cell culture. Surprisingly, however, knock-out mouse embryos deficient for midkine are phenotypically normal, which suggests functional redundancy by related growth factors. During adult stages, on the other hand, midkine knock-out mice develop striking deficits in neuroprotection and regeneration after drug-induced neurotoxicity and injury. Yet, the detailed mechanisms by which midkine controls neuron formation, differentiation and maintenance remain unclear. Recent studies in zebrafish and chick have provided important insight into the role of midkine and its putative receptor Anaplastic lymphoma kinase in cell cycle control in the central and peripheral nervous systems. A recent structural analysis of zebrafish midkine furthermore revealed essential protein domains required for biological activity that serve as promising novel targets for future drug designs. This review will summarize latest findings in the field that help to better understand midkine's diverse roles in nervous system formation and maintenance.
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