Ocular disorders are common in the human population since they are mostly compatible with life and reproduction but can be debilitating. The anterior segment of the vertebrate eye is a complex arrangement of interdependent tissues of different embryonic origins. Despite its crucial role in normal vision, relatively little is currently known about the mechanisms of anterior segment development but transcription factors may provide the necessary cues. We identified a new family of homeobox-containing transcription factor genes, PITX, and showed that these genes play a crucial role in anterior segment and lens development in mammals. In particular, we demonstrated that mutations in the human PITX3 gene are responsible for several developmental anterior segment disorders associated with glaucoma, corneal opacities and cataracts. We also recently identified a mutation in the mouse Pitx3 gene that is a likely cause of disturbed ocular development in aphakia mouse, which is characterized by small eyes lacking a lens and anterior chamber. PITX3/Pitx3 is a transcription factor gene and therefore represents an important component of the cascade of genes controlling development and provides a unique tool to study the molecular control of the development of the anterior segment of the eye in mammals. Identification of other genes involved in this cascade is of high priority. In this application we focus on the dissection of developmental pathways involving the PITX3/Pitx3 gene.
In aim 1, we propose to identify promoter and other regulatory elements of ocular expression of the PITX3/Pitx3 genes.
In aim 2, we will identify interacting factors of Pitx3 proteins.
In aim 3, we propose to identify the downstream genes of Pitx3. And finally, in aim 4, the genetic analysis of the identified components of PITX3 pathway will be performed in families affected with various anterior segment anomalies. The outcome of this study will improve our understanding of the mechanism of anterior segment development and identify the novel factors that are themselves likely to be responsible for a spectrum of human ocular disorders. This will lead to superior diagnosis, treatment and prevention of these debilitating conditions in the future.
| Sorokina, Elena A; Muheisen, Sanaa; Mlodik, Nevin et al. (2011) MIP/Aquaporin 0 represents a direct transcriptional target of PITX3 in the developing lens. PLoS One 6:e21122 |
| Reis, Linda M; Tyler, Rebecca C; Schneider, Adele et al. (2010) FOXE3 plays a significant role in autosomal recessive microphthalmia. Am J Med Genet A 152A:582-90 |
| Brémond-Gignac, Dominique; Bitoun, Pierre; Reis, Linda M et al. (2010) Identification of dominant FOXE3 and PAX6 mutations in patients with congenital cataract and aniridia. Mol Vis 16:1705-11 |
| Schneider, Adele; Bardakjian, Tanya; Reis, Linda M et al. (2009) Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet A 149A:2706-15 |
| Reis, Linda M; Tyler, Rebecca C; Abdul-Rahman, Omar et al. (2008) Mutation analysis of B3GALTL in Peters Plus syndrome. Am J Med Genet A 146A:2603-10 |
| Sakazume, Satoru; Sorokina, Elena; Iwamoto, Yoshiki et al. (2007) Functional analysis of human mutations in homeodomain transcription factor PITX3. BMC Mol Biol 8:84 |
| Zinkevich, Natalya S; Bosenko, Dmitry V; Link, Brian A et al. (2006) laminin alpha 1 gene is essential for normal lens development in zebrafish. BMC Dev Biol 6:13 |
| Maciolek, Nicole L; Alward, Wallace L M; Murray, Jeffrey C et al. (2006) Analysis of RNA splicing defects in PITX2 mutants supports a gene dosage model of Axenfeld-Rieger syndrome. BMC Med Genet 7:59 |
| Semina, Elena V; Bosenko, Dmitry V; Zinkevich, Natalya C et al. (2006) Mutations in laminin alpha 1 result in complex, lens-independent ocular phenotypes in zebrafish. Dev Biol 299:63-77 |
| Hjalt, Tord A; Semina, Elena V (2005) Current molecular understanding of Axenfeld-Rieger syndrome. Expert Rev Mol Med 7:1-17 |
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