The midkine family of growth factors: diverse roles in nervous system formation and maintenance
Open accessAbstract
Midkines are heparin‐binding growth factors involved 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, mouse embryos deficient for midkine (knockout mice) are phenotypically normal, which suggests functional redundancy by related growth factors. During adult stages, on the other hand, midkine knockout mice develop striking deficits in neuroprotection and regeneration after drug‐induced neurotoxicity and injury. 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 the diverse roles of midkine in nervous system formation and maintenance. Linked Articles: This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐4
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Midkine was highly upregulated at the protein level despite being unchanged in the snRNA-seq analysis.
“proteins such as the neurotrophic factor Midkine25, were found to be highly upregulated, despite being unchanged in our snRNA-seq analysis.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [25]
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Zhou, Y., Song, W. M., Andhey, P. S., Swain, A., Levy, T., Miller, K. R., Poliani, P. L., Cominelli, M., Grover, S., Gilfillan, S., et al. (2020) · Nature Medicine · doi:10.1038/s41591-019-0695-9 · Cited by 1,150 · see citing works
- Authors
- Winkler, C., & Yao, S.
- Affiliations
- National University of Singapore (SG)
- Corresponding author
- Winkler, C
- ORCID
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2014-01-24
- Volume
- 171
- Issue
- 4
- Pages
- 905-912
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3925029
- OpenAlex
- W1941666251
- Cited by
- 72
- References
- 60
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 6 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 4 · 2014: 3
- FWCI
- 0.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Singapore Ministry of Education-Academic Research Fund (R-154-000-478-112)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- midkine, heparin-binding growth factors, neurotrophic factors, brain development, neuroprotection, neuronal regeneration, anaplastic lymphoma kinase, functional redundancy, drug-induced neurotoxicity, cell cycle regulation, zebrafish, chick embryo, protein structure, therapeutic target
- MeSH terms
- Midkine, Animals, Humans, Membrane Glycoproteins, Nerve Regeneration, Nervous System, Neurons, Cytokines, Receptors, Growth Factor
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