Midkine is neuroprotective and influences glial reactivity and the formation of Müller glia-derived progenitor cells in chick and mouse retinas. 2021

Warren A Campbell, and Amanda Fritsch-Kelleher, and Isabella Palazzo, and Thanh Hoang, and Seth Blackshaw, and Andy J Fischer
Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

Recent studies suggest midkine (MDK) is involved in the development and regeneration of the zebrafish retina. We investigate the expression patterns of MDK and related factors, roles in neuronal survival, and influence upon the formation of Müller glia-derived progenitor cells (MGPCs) in chick and mouse model systems. By using single-cell RNA-sequencing, we find that MDK and pleiotrophin (PTN), a MDK-related cytokine, are upregulated by Müller glia (MG) during later stages of development in chick. While PTN is downregulated, MDK is dramatically upregulated in mature MG after retinal damage or FGF2 and insulin treatment. By comparison, MDK and PTN are downregulated by MG in damaged mouse retinas. In both chick and mouse retinas, exogenous MDK induces expression of cFos and pS6 in MG. In the chick, MDK significantly decreases numbers dying neurons, reactive microglia, and proliferating MGPCs, whereas PTN has no effect. Inhibition of MDK-signaling with Na3 VO4 blocks neuroprotective effects with an increase in the number of dying cells and negates the pro-proliferative effects on MGPCs in damaged retinas. Inhibitors of PP2A and Pak1, which are associated with MDK-signaling through integrin β1, suppressed the formation of MGPCs in damaged chick retinas. In mice, MDK promotes a small but significant increase in proliferating MGPCs in damaged retinas and potently decreases the number of dying cells. We conclude that MDK expression is dynamically regulated in Müller glia during embryonic maturation, following retinal injury, and during reprogramming into MGPCs. MDK mediates glial activity, neuronal survival, and the re-programming of Müller glia into proliferating MGPCs.

UI MeSH Term Description Entries
D009457 Neuroglia The non-neuronal cells of the nervous system. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the BLOOD-BRAIN BARRIER and BLOOD-RETINAL BARRIER, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. Bergmann Glia,Bergmann Glia Cells,Bergmann Glial Cells,Glia,Glia Cells,Satellite Glia,Satellite Glia Cells,Satellite Glial Cells,Glial Cells,Neuroglial Cells,Bergmann Glia Cell,Bergmann Glial Cell,Cell, Bergmann Glia,Cell, Bergmann Glial,Cell, Glia,Cell, Glial,Cell, Neuroglial,Cell, Satellite Glia,Cell, Satellite Glial,Glia Cell,Glia Cell, Bergmann,Glia Cell, Satellite,Glia, Bergmann,Glia, Satellite,Glial Cell,Glial Cell, Bergmann,Glial Cell, Satellite,Glias,Neuroglial Cell,Neuroglias,Satellite Glia Cell,Satellite Glial Cell,Satellite Glias
D012160 Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the OPTIC NERVE and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the CHOROID and the inner surface with the VITREOUS BODY. The outer-most layer is pigmented, whereas the inner nine layers are transparent. Ora Serrata
D002645 Chickens Common name for the species Gallus gallus, the domestic fowl, in the family Phasianidae, order GALLIFORMES. It is descended from the red jungle fowl of SOUTHEAST ASIA. Gallus gallus,Gallus domesticus,Gallus gallus domesticus,Chicken
D000078792 Midkine A developmentally regulated, HEPARIN-binding secreted growth factor homologous to pleiotrophin (PTN). It regulates cell proliferation through its interaction with ANAPLASTIC LYMPHOMA KINASE (ALK) and is involved in the formation of NEOINTIMA following arterial injury. Amphiregulin-Associated Protein,Cytokine MK,Amphiregulin Associated Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013234 Stem Cells Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells. Colony-Forming Units,Mother Cells,Progenitor Cells,Colony-Forming Unit,Cell, Mother,Cell, Progenitor,Cell, Stem,Cells, Mother,Cells, Progenitor,Cells, Stem,Colony Forming Unit,Colony Forming Units,Mother Cell,Progenitor Cell,Stem Cell
D015027 Zebrafish An exotic species of the family CYPRINIDAE, originally from Asia, that has been introduced in North America. Zebrafish is a model organism for drug assay and cancer research. Brachydanio rerio,Danio rerio,B. rerio,D. rerio,Zebra Fish,Zebra Fishes,Zebra danio,Zebrafishes,D. rerios,Fishes, Zebra,Zebra danios,danio, Zebra
D049109 Cell Proliferation All of the processes involved in increasing CELL NUMBER including CELL DIVISION. Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D063928 Ependymoglial Cells The macroglial cells of EPENDYMA. They are characterized by bipolar cell body shape and processes that contact BASAL LAMINA around blood vessels and/or the PIA MATER and the CEREBRAL VENTRICLES. Muller cells of the RETINA are included based on similar microenvironmental contacts and morphology. Ependymoglial Cell,Muller Cell,Muller Glia Cells,Muller Glial Cells,Radial Glia,Radial Glial Cell,Retinal Muller Cell,Retinal Muller Glial Cells,Tanycyte,Muller Cells,Radial Glial Cells,Retinal Muller Cells,Tanycytes,Cell, Ependymoglial,Cell, Muller,Cell, Radial Glial,Cell, Retinal Muller,Cells, Ependymoglial,Cells, Muller,Cells, Muller Glia,Cells, Muller Glial,Cells, Radial Glial,Cells, Retinal Muller,Glia Cells, Muller,Glia, Radial,Glial Cell, Radial,Glial Cells, Muller,Glial Cells, Radial,Glias, Radial,Muller Cell, Retinal,Muller Cells, Retinal,Radial Glias

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