Primary defects in the lens underlie complex anterior segment abnormalities of thePax6heterozygous eye

Abstract

We describe lens defects in heterozygous small eye mice, and autonomous deficiencies of Pax6 ؉/؊ cells in the developing lens of Pax6 ؉/؉ 7 Pax6 ؉/؊ chimeras. Two separate defects of the lens were identified by analyzing the distribution of heterozygous cells in chimeras: Pax6 ؉/؊ cells are less readily incorporated into the lens placode than wild type, and those that are incorporated into the lens are not maintained efficiently in the proliferating lens epithelium. The lens of chimeric eyes is, therefore, predominantly wild type from embryonic day 16.5 onwards, whereas heterozygous cells contribute normally to all other eye tissues. Eye size and defects of the iris and cornea are corrected in fetal and adult chimeras with up to 80% mutant cells. Therefore, these aspects of the phenotype may be secondary consequences of primary defects in the lens, which has clinical relevance for the human aniridia (PAX6 ؉/؊ ) phenotype.

Pax6 is misexpressed in Sox1 null lens fiber cells

“…4D-D', pointed appearance) although the phenotype was most pronounced in the Sox1 −/− ; Pax6 Sey/+ AEL. This is consistent with the findings of Collinson et al (2001) that Pax6 Sey/+ cells are preferentially lost from the AEL between E12.5 and E16.5 in Pax6 Sey/+ ↔ Pax6 +/+ chimeric mice. Additional evidence that this additive defect derives from a defect in the AEL comes from lenses evaluated at E15.5.…”

Cell autonomous roles for AP‐2α in lens vesicle separation and maintenance of the lens epithelial cell phenotype

“…In addition to Tcfap2a, several other genetic mutations in mice and humans have been shown to result in corneal-lenticular adhesions (lens stalk) and in humans this often referred to as Peter's anomaly (Theiler and Varnum, 1981;Hill et al, 1991;Favor et al, 1997;Prosser and van Heyningen, 1998;Blixt et al, 2000;Brownell et al, 2000;Semina et al, 2000;Collinson et al, 2001;Rieger et al, 2001). Some of these genes, such as Pax6, Foxe3, and Pitx3 are known to act in combination or in a linear pathway (Chow and Lang, 2001).…”

Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases

“…(44)(45)(46) Humans with heterozygote mutations in PAX6 exhibit the phenotype aniridia, a panocular disease that is associated with iris hypoplasia, corneal opacification, cataract and foveal dysplasia. The high and continuous expression of Pax6 in cells that derive from surface ectoderm and optic cup (lens, corneal epithelium, iris, and ciliary epithelium) appears to be required for the expression of transcription factors (Six3, c-Maf, MafA/L-Maf and Prox1, (62,64) structural genes (crystallins and cell adhesion molecules), (65)(66)(67)(68)(69) and signaling molecules, which are critical for the morphogenesis of those tissues, and subsequently for the migration of neural crest cells into the eye by inductive processes(53) (Fig. 5).…”

“…(93) Retinoic acid has recently been shown as an environmental modifier of velo-cardio-facial (DiGeorge) syndrome, which is caused by defects in neural crest cell migration,(94) raising the intriguing possibility that the variability of the PAX6 gene dosage effect might be modified via retinoids. Similar to lens formation, the candidate genes that are under direct or indirect influence of Pax6 in neural crest cells might include cell adhesion molecules, (66)(67)(68)(69) although direct molecular evidence for this is still lacking. Since the expression of Pax6 is weak in neural crest cells, many Pax6 target genes, even those with high-affinity Pax6-binding sites (see Fig.…”