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Abstract
BackgroundThe roles of the Hedgehog (Hh) pathway in controlling vertebrate retinal development have been studied extensively; however, species- and context-dependent findings have provided differing conclusions. Hh signaling has been shown to control both population size and cell cycle kinetics of proliferating retinal progenitors, and to modulate differentiation within the retina by regulating the timing of cell cycle exit. While cell cycle exit has in turn been shown to control cell fate decisions within the retina, a direct role for the Hh pathway in retinal cell fate decisions has yet to be established in vivo.ResultsTo gain further insight into Hh pathway function in the retina, we have analyzed retinal development in leprechaun/patched2 mutant zebrafish. While lep/ptc2 mutants possessed more cells in their retinas, all cell types, except for Müller glia, were present at identical ratios as those observed in wild-type siblings. lep/ptc2 mutants possessed a localized upregulation of GFAP, a marker for 'reactive' glia, as well as morphological abnormalities at the vitreo-retinal interface, where Müller glial endfeet terminate. In addition, analysis of the over-proliferation phenotype at the ciliary marginal zone (CMZ) revealed that the number of proliferating progenitors, but not the rate of proliferation, was increased in lep/ptc2 mutants.ConclusionOur results indicate that Patched2-dependent Hh signaling does not likely play an integral role in neuronal cell fate decisions in the zebrafish retina. ptc2 deficiency in zebrafish results in defects at the vitreo-retinal interface and Müller glial reactivity. These phenotypes are similar to the ocular abnormalities observed in human patients suffering from Basal Cell Naevus Syndrome (BCNS), a disorder that has been linked to mutations in the human PTCH gene (the orthologue of the zebrafish ptc2), and point to the utility of the lep/ptc2 mutant line as a model for the study of BCNS-related ocular pathologies. Our findings regarding CMZ progenitor proliferation suggest that, in the zebrafish retina, Hh pathway activity may not affect cell cycle kinetics; rather, it likely regulates the size of the retinal progenitor pool in the CMZ.
Highlights
The roles of the Hedgehog (Hh) pathway in controlling vertebrate retinal development have been studied extensively; species- and context-dependent findings have provided differing conclusions
We assayed the expression of phosphohistone H3 (PH3) and these analyses revealed that the proportion of ciliary marginal zone (CMZ) progenitors occupying the M phase of the cell cycle increased by approximately 34% in lep/ptc2 retinas at 64hpf, when compared to their phenotypically wild-type siblings (Figure 7E, F, H)
Retinal patterning is normal in lep/ptc2 mutants Characterization of lep/ptc2 retinas with respect to cell type composition revealed that over-activity of the Hh pathway did not affect retinal patterning
Summary
The roles of the Hedgehog (Hh) pathway in controlling vertebrate retinal development have been studied extensively; species- and context-dependent findings have provided differing conclusions. Hh signaling has been shown to control both population size and cell cycle kinetics of proliferating retinal progenitors, and to modulate differentiation within the retina by regulating the timing of cell cycle exit. While cell cycle exit has in turn been shown to control cell fate decisions within the retina, a direct role for the Hh pathway in retinal cell fate decisions has yet to be established in vivo. While the role of the Hh pathway in cell cycle exit and differentiation of retinal progenitors is well described, comparatively less is known about its possible influence on cell fate decisions. Shh has been shown to promote early cell cycle exit in the Xenopus retina [9]; a direct role of the Hh pathway in dictating retinal cell fate has yet to be established in vivo
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