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A. Calinescu, P. H. Hitchcock; Expression of Midkine-a in Horizontal Cells Is Regulated by the Circadian Clock and May Modulate Circadian Neurogenesis in the Zebrafish Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):184.
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© ARVO (1962-2015); The Authors (2016-present)
In the adult zebrafish retina neurogenesis persists in two regions that harbor stem cell niches: the ciliary marginal zone, at the border between the retina and iris, and in the inner nuclear layer in central retina, where resident stem cells proliferate and give rise exclusively to rod photoreceptors. Upon injury, the retina of teleosts can regenerate in a process that largely recapitulates cellular and molecular events that occur during development. Little is known about secreted signaling factors that regulate persistent and regenerative neurogenesis. We found that the heparin-binding growth factor midkine-a (mdka) is expressed in neurogenic stem cells and their progeny in the retina both during development and regeneration. In addition mdka is constitutively expressed in horizontal cells. In other teleosts a diurnal rhythm of rod precursor proliferation has been described (Chiu et. al, 1995 , Brain Res. 673(1):119, Julian et. al, 1998, J Comp Neurol. 394(3):271). We tested whether or not proliferation in the zebrafish retina is regulated by the circadian clock and if mdka expression correlates with this persistent neurogenesis.
Zebrafish were housed in complete darkness for 24 hours. Retinal RNA, protein and eyecups were harvested at 4 hour intervals and analyzed for PCNA expression by real-time QRTPCR and mdka mRNA expression by in situ hybridization and Midkine-a protein synthesis by western blot analysis.
Expression of PCNA in the zebrafish retina is relatively low during the subjective day and increases during the subjective night. In situ hybridization reveals a circadian rhythm of mdka expression in horizontal cells that reaches maximum during subjective day and minimum during subjective night. Western blot analysis shows Midkine-a protein levels follow the same circadian pattern.
Proliferation in the retina follows a circadian rhythm. Expression of mdka in horizontal cells is also regulated by the circadian clock. PCNA and mdka expression are 12 hours out of phase. Because mdka is a secreted factor present in retinal stem cells during both development and photoreceptor regeneration (manuscript in preparation) and is expressed in a circadian manner in horizontal cells, which lie adjacent to proliferating rod precursors, we hypothesize that Midkine-a may modulate the circadian rhythm of retinal neurogenesis in the zebrafish retina.
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