Relationship of Pax6 Activity Levels to the Extent of Eye Development in the Mouse, Mus musculus

Abstract

In this study we extend the mouse Pax6 mutant allelic series to include a homozygous and hemizygous viable hypomorph allele. The Pax6 132-14Neu allele is a Phe272Ile missense mutation within the third helix of the homeodomain. The mutant Pax6 homeodomain shows greatly reduced binding activity to the P3 DNA binding target. Glucagon-promoter activation by the entire mutant Pax6 product of a reporter gene driven by the G1 paired and homeodomain DNA binding target was slightly increased. We constructed mutant Pax6 genotypes such that Pax6 activity ranged between 100 and 0% and show that the extent of eye development is progressively reduced as Pax6 activity decreased. Two apparent thresholds identify three groups in which the extent of eye development abruptly shifted from complete eye at the highest levels of Pax6 to a rudimentary eye at intermediate levels of Pax6 to very early termination of eye development at the lowest levels of Pax6. Of the two Pax6-positive regions that participate in eye development, the surface ectoderm, which develops into the lens vesicle and the cornea, is more sensitive to reduced levels of Pax6 activity than the optic vesicle, which develops into the inner and outer retinal layers. T HE transcription factor Pax6 belongs to the family of paired-box-containing genes and is highly conserved over a wide range of phyla within the kingdom animalia. The mouse Pax6 gene encodes a protein with DNA binding paired and homeodomains separated by a linker region, and a C-terminal proline-, serine-, and threonine-rich transcriptional activation domain (Walther and Gruss 1991;Glaser et al. 1994). By mutant analysis Pax6 was shown to function in the development of the eye (Theiler et al.

Analysis of Pax6 Contiguous Gene Deletions in the Mouse, Mus musculus, Identifies Regions Distinct from Pax6 Responsible for Extreme Small-Eye and Belly-Spotting Phenotypes

“…Body weight and gross eye morphology: Eye morphology was assessed as previously described (Favor et al 2001(Favor et al , 2008. P35 heterozygous mutant and wild-type littermates were ophthalmologically examined by slit lamp microscopy and categorized for the degree of lens/corneal opacity and extreme microphthalmia.…”

Clinical and experimental advances in congenital and paediatric cataracts

“…Usually, the expressivity of heterozygous Pax6 mutations is variable, with individuals exhibiting a range of phenotypes from small anterior polar cataracts to the more visually significant anterior polar lens opacities, corneal adhesions, iris abnormalities and microphthalmia. Furthermore, the degree of phenotype expressed between the two eyes of the same person is variable ( [95] and references therein).…”

Pax6 in Collembola: Adaptive evolution of eye regression

“…It was further confirmed that the highly conserved Pax6 is a universal master control gene for eye development in the animal kingdom. Similar to the studied Pax6 genes in zebrafish 42 , Drosophila 36 , quail 43 , mouse [44][45][46] , and human 21,47,48 , the non-conserved C-terminus of the collembolan Pax6 is vital for protein transactivation ability. In our study, gradual deletions from the C-terminal end of collembolan Pax6 led to a gradual loss of activity in inducing ectopic eyes on Drosophila (Fig.…”