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Paired box 6 (PAX6) is a member of the PAX multigene family of transcription factors: this family regulates embryonic differentiation. Nine unlinked PAX genes dispersed throughout the genome encode proteins that each include a 128-amino-acid sequence-specific highly conserved DNA-binding domain, the Paired box, which can regulate the expression of other genes [1]. PAX6 also contains another common DNA-binding element: the homeobox that encodes a 60-amino-acid homeodomain responsible for target sequence recognition [2]. The paired domain and homeodomain interact cooperatively to recognise multiple DNA binding sites [3]. Pax6 is expressed in the developing nervous system and in developing eyes [4], and also has important functions in the development of the endocrine pancreas. Genetic studies indicate that all eyes share a similar developmental cascade: mutations in Pax6 disrupt eye development in both mammals and insects [4]. Pax6 appears to be necessary for the correct execution of beta cell differentiation [5] and is essential for the normal expression of insulin [6]. PAX6 is required for the differentiation of pancreatic islet alpha cells, and competes with PAX4 in binding to a common element in the glucagon, insulin and somatostatin promoters [7]. Mice lacking both Pax4 and Pax6 fail to develop any mature endocrine cells, suggesting that both genes are required for endocrine development of the pancreas [8]. As well as binding to a common element in the glucagon, insulin and somatostatin promoters, Pax6 also transactivates the glucagon and insulin promoters [6]. Pax6-deficient mice have reductions in both insulinand glucagon-expressing cells. Human PAX6 is transcribed as a 2.7 kb mRNA and encodes a 422-amino-acid protein. PAX6 extends to over 22 kb: it contains 14 exons and intron sequences and is highly conserved among vertebrates and lower animals. Mutations in PAX6 in humans cause aniridia type II, a bilateral panocular disorder characterised by a complete or partial absence of the iris and fovea, and malformations of the lens and anterior chamber [2]. About one-third of the cases are sporadic and two-thirds are familial, with autosomal dominant inheritance and high penetrance. There is a PAX6 dosage effect in aniridia, ranging from mild loss of visual acuity and cataracts, to severe nervous system defects and anophthalmia [7]. Using magnetic resonance imaging techniques and smell testing, Sisodiya et al. [9] showed with that reduced olfaction was present in a large proportion of aniridia patients, indicating that PAX6 haploinsufficiency causes more widespread human neurodevelopmental anomalies. Yasuda et al. [10] were the first to demonstrate that carriers of the PAX6 mutation might have abnormal glucose Diabetologia (2009) 52:381–384 DOI 10.1007/s00125-008-1251-1

Not for the eyes only: PAX6 and glucose metabolism