PT  - JOURNAL ARTICLE
AU  - Warren A. Campbell
AU  - Amanda Fritsch-Kelleher
AU  - Isabella Palazzo
AU  - Thanh Hoang
AU  - Seth Blackshaw
AU  - Andy J. Fischer
TI  - Midkine in chick and mouse retinas: neuroprotection, glial reactivity and the formation of Müller glia-derived progenitor cells
AID  - 10.1101/2020.08.12.248245
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.12.248245
4099  - http://biorxiv.org/content/early/2020/08/12/2020.08.12.248245.short
4100  - http://biorxiv.org/content/early/2020/08/12/2020.08.12.248245.full
AB  - Recent studies have shown that midkine (MDK), a basic heparin-binding growth factor, is involved in the development and regeneration of the zebrafish retina. However, very little is known about MDK in the retinas of warm-blooded vertebrates. 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 (scRNA-seq), we find that MDK and related factors are dynamically expressed by maturing MG and by MG in retinas damaged by NMDA or treated with insulin and FGF2. Interestingly, MDK is significantly up-regulated by MG in damaged chick retinas, but down-regulated by MG in damaged mouse retinas. In both chick and mouse retinas, exogenous MDK selectively up-regulates cFOS and pS6 (a readout of mTOR-signaling) in Müller glia. In the chick, intraocular injections of MDK before injury decrease numbers of dying cells, decrease microglial reactivity, decrease the accumulation of Non-astrocytic Inner Retinal Glial (NIRG) cells, and decrease numbers of proliferating MGPCs. Addition of MDK signaling inhibitor Na3VO4 following retinal injury reverses these effects to increase the number of dying cells, accumulation of NIRG cells, and decrease the number of proliferating MGPCs. Inhibitors of PP2A and Pak1 had specific inhibitory effects on MGPC formation. In mice, MDK administration with NMDA damage drives a small but significant increase in MGPCs. We conclude that MDK expression is dynamically regulated in reactive Müller glia and during reprogramming into MGPCs. MDK acts to coordinate glial activity, neuronal survival, and may act in an autocrine manner to influence the re-programming of Müller glia into proliferating MGPCs.Competing Interest StatementThe authors have declared no competing interest.