1. Department of Biological Sciences, Warwick University, Coventry CV4 7AL, UK
2. These authors contributed equally to this work.

Correspondence to: Nicholas Dale^1,2Elizabeth A. Jones^1,2 Correspondence and requests for materials should be addressed to N.D. (Email: n.e.dale@warwick.ac.uk) or E.A.J. (Email: elizabeth.jones@warwick.ac.uk).

A conserved network of eye field transcription factors (EFTFs) underlies the development of the eye in vertebrates and invertebrates¹. To direct eye development, Pax6, a key gene in this network^{2, 3}, interacts with genes encoding other EFTFs such as Rx1 and Six3 (refs 4–6). However, the mechanisms that control expression of the EFTFs remain unclear⁷. Here we show that purine-mediated signalling triggers both EFTF expression and eye development in Xenopus laevis. Overexpression of ectonucleoside triphosphate diphosphohydrolase 2 (E-NTPDase2)⁸, an ectoenzyme that converts ATP to ADP⁹, caused ectopic eye-like structures, with occasional complete duplication of the eye, and increased expression of Pax6, Rx1 and Six3. In contrast, downregulation of endogenous E-NTPDase2 decreased Rx1 and Pax6 expression. E-NTPDase2 therefore acts upstream of these EFTFs. To test whether ADP (the product of E-NTPDase2) might act to trigger eye development through P2Y1 receptors, selective in Xenopus for ADP^{10, 11}, we simultaneously knocked down expression of the genes encoding E-NTPDase2 and the P2Y1 receptor. This could prevent the expression of Rx1 and Pax6 and eye formation completely. We next measured ATP release^{12, 13, 14} in the presumptive eye field, demonstrating a transient release of ATP at a time that could plausibly trigger (once converted to ADP) expression of the EFTFs. This surprising role for transient purine-mediated signalling in eye development may be widely conserved, because alterations to the locus of E-NTPDase2 on human chromosome 9 cause severe head and eye defects, including microphthalmia^{15, 16, 17, 18}. Our results suggest a new mechanism for the initiation of eye development.

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