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| Eye development: Purinergic receptor signaling regulates Pax6
Eye development in Xenopus is coordinated by the hydrolase E-NTPDase2 and the P2Y1 purinergic receptor, which promotes the expression of the transcription factor Pax6. Eye development in vertebrates and invertebrates is directed by a complex network of eye field transcription factors. One of these transcription factors, Pax6, is necessary and sufficient to direct eye development in Xenopus. However, its regulation is not yet understood. In Nature, Massé et al. identify a novel pathway in which ADP-mediated stimulation of the P2Y1 purinergic receptor promotes expression of Pax6 and regulates Xenopus eye development.
The diphosphohydrolase E-NTPDase2 generates ADP by hydrolyzing ATP. Mutations at the E-NTPDase2 locus in humans have been linked to microphthalmia, a disease characterized by small eyes. To investigate the role of E-NTPDase2 function in vertebrate eye development, E-NTPDase2 mRNA was injected into Xenopus blastocysts. Overexpression of E-NTPDase2 generated ectopic eye structures at sites that correlated to the initial injection site — that is, injection at the dorsal side of the blastocyst resulted in an eye structure formed at the head of the mature embryo, but injection at the ventral side created an eye structure in the abdomen or tail of the embryo. This finding suggests that E-NTPDase2 is sufficient to direct eye development at ectopic sites lacking normal contextual cues. E-NTPDase2 activity also correlated with Pax6 expression, as antisense morpholino oligonucleotide-mediated depletion of E-NTPDase2 significantly curtailed Pax6 expression. This effect could be rescued by exogenous expression of morpholino-insensitive mouse E-NTPDase2. ADP produced by E-NTPDase2 is a ligand for the purinergic receptor P2Y1. Given that E-NTPDase has a profound effect on eye development, could the P2Y1 receptor be important for this function as well? Analogous to E-NTPDase2, expression of a morpholino against P2Y1 reduced eye size. Genetic depletion of P2Y1 and E-NTPDase2 completely ablated eye formation, while ectopic overexpression of both proteins created several additional eye-like structures in the embryo. The severity of the double mutant phenotype indicates a synergistic relationship between E-NTPDase2 and P2Y1. Indeed, E-NTPDase2, P2Y1 and Pax6 appear to reside in a common signaling pathway, as the ablated eye phenotype that was induced by loss of P2Y1/E-NTPDase2 could be partially rescued by Pax6 overexpression. P2Y1 is likely an intermediary in the pathway, as agonist-induced activation of P2Y1 restored Pax6 mRNA levels in an E-NTPDase2-deficient background, and application of a P2Y1 antagonist diminished the E-NTPDase2-mediated upregulation of Pax6 mRNA. Eye field transcription factors, E-NTPDases and purinergic receptors are well conserved among vertebrates and invertebrates. The link between E-NTPDase2 and microphthalmia suggests that the novel pathway described by Massé et al. is likely conserved in humans. Emily J. Chenette
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