Dysgenetic lens (Foxe3dyl) was originally characterized as an autosomal recessive mouse mutant but Foxe3 haploinsufficiency can also yield a similar phenotype characterized by defective lens development and cataracts. Homozygotes are viable and fertile. The most prominent abnormality is the irregular shape and reduced size of the lens. The pupil is also smaller and exhibits abnormal reactivity. The major morphological hallmark of homozygous Foxe3dyl mice is the persistent attachment of the lens to the corneal epithelium. The iris can also be fused with the lens but the retina remains unaffected. The lens contains fewer secondary fibers but when present, these fibers are very disorganized and the tissue contains large vacuoles. The developing lens initially forms properly as the lens placode is induced within the anterior neural ectoderm but around embryonic day 10 the mutant lens vesicle does not completely close and detach from the ectoderm as is seen normally. Cells of the posterior epithelium of the dysgenetic lens exit the cell cycle and enter terminal differentiation prematurely while anterior cells of the lens surface lack a normal proliferative capacity and die by apoptosis. Together, the observations indicate that Foxe3 is involved in suppressing differentiation and promoting cell survival and proliferation. Defects outside of the eye have not been identified in Foxe3dyl mutants.
Foxe3 expression is correlated with undifferentiated cells in the lens and therefore suggests the protein is a regulator of cell maturation. Dysgenetic lens cell differentiation was assessed using crystallin soluble protein markers which are abundantly expressed in the lens. While crystallin protein expression is not abolished, alpha- and beta-crystallins aberrantly appear in the developing mutant lens, implicating FOXE3 involvement in lens cell differentiation processes.
The human ortholog of Foxe3 has been identified and mutations have been characterized in patients with lens abnormalities and cataracts. The phenotype of Foxe3dyl/+ mice is variable and abnormalities of the lens/cornea are generally less severe than those found in homozygous mutants (penetrance ~40%). The heterozygous mutant phenotype resembles Peters' anomaly, a human disease bearing similar developmental ocular disorders. Peters' anomaly is not consistently associated with mutations in FOXE3 but it is generally concluded that FOXE3 activity is important for normal eye formation and dyl mice likely serve as a useful model for human anterior ocular disorders.
The search for molecules thatinduce and/or regulate Foxe3 expression in the eye has focused on two mutant models that affect normal eye formation. Embryos deficient for the homeobox gene Rax(also known as Rx) are unable to form optic vesicles and also do not express Foxe3 within surface ectoderm during development, suggesting that Foxe3 expression is dependent on signals originating from the optic vesicle. By contrast, expression of Foxe3 in the midbrain during Rx/rax mutant gestation is not altered, implying that induction is differentially regulated in a tissue specific manner. Another mutant that exhibits gross eye malformations is the small eye mutant Sey which results from a mutated Pax6 homeobox-containing gene. Here the lens is completely missing but the optic vesicle initially forms. Foxe3 expression is completely absent in Pax6Sey mutants; PAX6 activity in the ectoderm and optic vesicle, therefore, appears to be involved in normal Foxe3 expression.
Foxe3dyl arose spontaneously on the BALB/cHeA background in 1979. In January 1992, BALB/cHeA-Foxe3dyl/Foxe3dyl mutants were imported to The Jackson Laboratory from Somes Sanyal (Sanyal and Hawkins, 1979). The line was maintained by homozygous sibling mating. BALB/cHeA-Foxe3dyl/Foxe3dylembryos from homozygous parents were cryopreserved in 1992.
|Allele Name||dysgenetic lens|
|Gene Symbol and Name||Foxe3, forkhead box E3|
|Strain of Origin||BALB/cLiA|
|Molecular Note||Two missense mutations in the sequences encoding the forkhead domain were shown to co-segregate with the dyl phenotype: two C-to-T transitions at coding nucleotides 277 and 293 that change codons 93 and 98 from phenylalanine to leucine and serine respectively (p.F93L, p.F98S). These mutations are in a region of the protein thought to be critical for DNA binding.|
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