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X.-J. Yang, X.-M. Zhang, T. Hashimoto; Effects of the Proneural Transcription Factor Ath5 on Cell Cycle Progression and Neuronal Fate Specification. Invest. Ophthalmol. Vis. Sci. 2010;51(13):719.
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© ARVO (1962-2015); The Authors (2016-present)
Vertebrate retinal development is regulated by both cell-extrinsic cues and cell-intrinsic factors. Previously, we have shown that Sonic Hedgehog (Shh) secreted by retinal ganglion cell (RGC) negatively regulates RGC production behind the neurogenic wave front in the developing chicken and mouse retinas. We have also demonstrated that Shh signals predominantly suppress the bHLH transcription factor Ath5 required for RGC fate specification. The purpose of this study is to further investigate mechanisms by which Shh signals influence nuclear transcription factors, and functions of the proneural gene Ath5 in cell fate specification and cell cycle regulation.
Retroviral viral vectors were used to express Shh or Ath5 and to infect the embryonic chicken retina in vivo. Effects of perturbing Shh and Ath5 expression were analyzed by in situ hybridization, RT-PCR, immunocytochemistry, and flow cytometry.
Ectopic expression of Ath5 ahead of the neurogenic wave front results in sporadic and precocious RGC production. In contrast, misexpression of Shh ahead of the neurogenic wave does not accelerate the propagation of the neurogenic wave or induce precocious RGC formation. During early chicken retinal development, elevated Shh signals stimulate Hairy2 expression and suppress Ath5 expression. Forced expression of Ath5 behind the neurogenic wave front results in a dramatic overproduction of RGCs and a mild increase of photoreceptor cells. In addition, forced Ath5 expression lead to decreased proliferation of retinal progenitor cells by reducing S phase reentry and promoting cell cycle exit.
Ectopic expression of the proneural factor Ath5 but not Shh can induce precocious RGC determination among a subset of preneurogenic progenitors. In the neurogenic retina, Shh positively regulates the bHLH factor Hairy2 but suppresses Ath5. Elevated Ath5 expression in neurogenic progenitors significantly alters cell cycle progression and facilitates specific neuronal production.
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