Some of the PITX2 target genes identified here (
Table 1) have functions relevant to glaucoma pathology. For example, levels of pyruvate dehydrogenase phosphatase (
PDP2) are decreased in response to the stresses of starvation and diabetes resulting in hyperphosphorylation and inactivation of the pyruvate dehydrogenase complex.
49,50 Our results also show that
SLC13A3 is a direct target of PITX2 regulation.
SLC13A3 encodes a transmembrane protein, NaDC3, that acts as a Na
+/dicarboxylate cotransporter. Mammalian NaDC3 is expressed in the liver, kidney,
51 brain,
52 eye, and optic nerve,
30,53 and here we demonstrate the localization of zebrafish
slc13a3 in similar tissues. Most notably, the pattern of its expression in the periocular mesenchyme and anterior ocular segment at different stages of development overlaps remarkably well with that of zebrafish
pitx2.
38,39 In situ hybridization of adult mouse eye showed that NaDC3 mRNA is present in anterior and posterior segments. A postulated role of NaDC3 in kidney cells is to transport GSH,
31 one of the main defense mechanisms of the human body against oxidative stress. Aqueous humor of glaucoma patients presents with reduced total antioxidant potential
54 and decreased plasma GSH levels.
55 SLC13A3 is also hypothesized to contribute to the maintenance of visual function because of its role in transporting the neuronal metabolite N-acetylaspartic acid (NAA) across the plasma membrane in ocular tissues.
30 Mutations in the gene encoding aspartoacylase, which hydrolyses intracellular NAA, cause Canavan disease, an autosomal recessive disorder associated with optic neuropathy, mental retardation, and brain degeneration.
56 The potential roles of
SLC13A3 in oxidative stress and in the optic neuropathy caused by Canavan disease indicate
SLC13A3 as a good candidate for involvement in glaucoma.