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Caroline Walsh, Peter Hitchcock; The function of Progranulin-a, a microglia-specific growth factor, during vertebrate retinal development. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3755.
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Progranulin is an evolutionarily conserved secreted growth factor well established for its role in embryogenesis, tumor development and wound repair. Although much is known about progranulin activity in non-neuronal tissues, the functions of progranulin within the central nervous system (CNS) are not well understood. In humans, mutations in the progranulin gene (GRN) cause neurodegeneration. In zebrafish, progranulin-a (Pgrn-a), syntenic to GRN, is expressed exclusively by peripheral macrophages and CNS microglia, and is strongly upregulated in retinal microglia after the selective death and regeneration of photoreceptors. There is a gap in our knowledge, however, regarding the functions of progranulin during developmental neurogenesis. Therefore, the purpose of this study was to determine how Pgrn-a regulates vertebrate nervous system development, using the zebrafish retina as a model.
The work presented here combined reverse genetics and quantitative morphometric approaches, including in vivo and in vitro assays of cell proliferation and differentiation, flow cytometry, and expression studies, to elucidate the details by which Pgrn-a regulates retinal progenitor cell cycle.
Knock down of Pgrn-a synthesis in zebrafish embryos results in the absence of neuronal differentiation in the retina, maintenance of retinal progenitors in a proliferating state, and altered cell cycle kinetics. Collectively, our data show Pgrn-a loss-of-function (LOF) lengthens retinal progenitor cell cycle and Pgrn-a gain-of-function (GOF) accelerates retinal progenitor cell cycle. Specifically, the proportion of cells undergoing mitosis in the retina covaries with Pgrn-a levels. Relative to controls G2-phase is significantly slower following Pgrn-a LOF and significantly faster following Pgrn-a GOF. Similarly, the total cell cycle length and S-phase duration is significantly longer following Pgrn-a LOF and significantly shorter following Pgrn-a GOF. The expression of cell cycle promoters/kinases is correspondingly altered in experimental embryos.
These data suggest that for retinal progenitors Pgrn-a functions to govern the transition from proliferation to differentiation, and that in the vertebrate retina, microglia-derived growth factors regulate aspects of developmental neurogenesis.
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