Although the functions of this domain are not yet fully understood, other OAR-containing proteins show that the OAR domain appears to perform an inhibitory function because the deletion of the domain results in increased DNA binding or the transactivation of target promoters. Additionally, the C-terminal region of other PITX proteins has multiple regulatory roles and is involved in specific proteinprotein interaction. In this study, we showed that the loss of the PITX3 OAR domain leads to the enhancement of PITX3 transcription and translation, which is most likely due to the obliteration of the anti-transcriptional activity associated with specific protein-protein interactions caused by the loss of the OAR domain. In addition, we showed that the expression of the downstream targets of PITX3 protein was affected in the miak mutants. We detected an enhanced binding reactivity of nuclear extracts from miak mice, compared to wild-type nuclear extracts, to both Foxe3 and Mip oligo probes, including bicoid elements, when assaying PITX3 binding EMSAs. Although we could not confirm whether the truncated PITX3 resulting from the miak mutation was included in the DNA-protein complex, this result suggests that the truncated PITX3 proteins can bind the bicoid elements of Foxe3 and Mip. These results suggest that the OAR domain has a role in the positive regulation of the expression of the downstream genes. MIP/AQP0 protein, which acts on the maintenance of lens fiber cells mediated by water channel activities, is a direct transcriptional target of the PITX3 homeodomain in the lens. A p.Gly220ProfsX94 mutation in PITX3 leads to a large reduction in Mip transcript. This result revealed that the OAR domain as well as the homeodomain is required for the normal transcription of Mip and that Mip expression is inhibited by the loss of OAR domain. Therefore, the interaction between the OAR domain and homeodomain of PITX3 protein may be essential for the normal expression of downstream genes such as Mip, Prox1 and Foxe3. Moreover, Medina-Martinez et al. reported the downregulation of the Cry genes in the lens of the Pitx3ak mutant. However, the expression of aA-crystallin was detected in the miak mutant. This difference in the expression pattern in aAcrystallin may represent variations in lens vesicle formation between Pitx3ak and miak mutants. a-crystallin is composed of two molecules, aA- and aB-crystallin, which are encoded by the Cryaa and Cryab genes, respectively. During the Dabrafenib embryonic period, Cryaa begins to be expressed on the lens cup at E10-10.5, while Cryab is first detected at E9.5 in the mouse lens. The later expression of these genes primarily occurs on the lens fiber and lens epithelial cells. Mammalian studies have shown that prenatal exposure to certain environmental stresses and chemical contaminants can lead to alterations in phenotypes in successive generations.