Functional Characterization of Non-Coding RNAs in the Mammalian Retina

Meola, Nicola (2011). Functional Characterization of Non-Coding RNAs in the Mammalian Retina. PhD thesis The Open University.



Long non-coding RNAs (IncRNAs) are emerging as regulators of a number of basic cellular pathways. Several IncRNAs are selectively expressed in the developing retina, although little is known about their functional role in this tissue. During my PhD thesis I characterized the expression pattern of three retinal-lncRNAs, namely Six3os, Otx2os and Vax2os in the developing mouse retina. Opposite Strand (OS) transcripts are transcribed in the opposite direction of protein-coding genes, in this case Six3, Otx2 and Vax2, respectively. Furthermore, I performed a comprehensive functional study for Vax2os1, the most abundant transcript from the Vax2os cluster, whose expression is restricted to the mouse ventral retina. I demonstrated that misexpression of Vax2os1, both in vitro and in vivo, determines cell cycle alterations in photoreceptor progenitor cells. In particular, the overexpression of Vax2os1 in the developing postnatal mouse retina caused an impaired cell cycle progression of photoreceptor progenitors toward their final committed fate and a consequent delay of their differentiation processes. At later developmental stages, this perturbation was accompanied by an increase of apoptotic events in the photoreceptor cell layer, in comparison with control retinas, without affecting the proper cell layering in the adult retina. Similar results were observed in mouse photoreceptor-derived 661W cells in which Vax2os1 overexpression resulted in an impairment of the cell cycle progression rate and cell differentiation. Based on these results, I conclude that Vax2os1 seems to ensure proper control of the cell cycle progression of photoreceptor progenitor cells in the ventral retina. Therefore, I propose Vax2os1 as the first example of IncRNA that acts as a cell cycle regulator in the mammalian retina during development.

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