Description

Strain Information

Type Coisogenic; Mutant Strain; Spontaneous Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse

Description

Dysgenetic lens (Foxe3^dyl) 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 Foxe3^dyl 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 Foxe3^dyl 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 Foxe3^dyl/+ 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 Pax6^Sey mutants; PAX6 activity in the ectoderm and optic vesicle, therefore, appears to be involved in normal Foxe3 expression.

Development
Foxe3^dyl arose spontaneously on the BALB/cHeA background in 1979. In January 1992, BALB/cHeA-Foxe3^dyl/Foxe3^dyl mutants were imported to The Jackson Laboratory from Somes Sanyal (Sanyal and Hawkins, 1979). The line was maintained by homozygous sibling mating. BALB/cHeA-Foxe3^dyl/Foxe3^dylembryos from homozygous parents were cryopreserved in 1992.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

	Anterior Segment Mesenchymal Dysgenesis; ASMD - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
	Peters Anomaly - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Foxe3^dyl/Foxe3⁺

        BALB/cLiA-Foxe3^dyl

• vision/eye phenotype
• abnormal anterior eye segment morphology (MGI Ref ID J:119940)
  • defects in anterior segments are observed, implying errors in cell differentiation occurring after lens vesicle closure
• abnormal corneal endothelium morphology (MGI Ref ID J:119940)
  • corneal endothelium is filled with large bubbles consisting of inflated extracellular space between endothelial cells
• abnormal corneal stroma morphology (MGI Ref ID J:119940)
  • stroma contains blood vessels, indicating hypoxia
  • stroma shows edema, with disorganized, loosely packed collagen fibers
• abnormal iris morphology (MGI Ref ID J:119940)
  • iris is more compact and lacks intricate channels of extracellular space which penetrate deeply into the wild-type iris
  • adherences are seen between iris and lens
  • iris is thinner and less well developed than in wild-type
• corneal adhesion to iris (MGI Ref ID J:119940)
  • adherences close filtration angle along parts of ocular circumference
• iris hypoplasia (MGI Ref ID J:119940)

Foxe3^dyl/Foxe3^dyl

        BALB/cLiA-Foxe3^dyl

• vision/eye phenotype
• abnormal ciliary body morphology (MGI Ref ID J:119940)
  • iris and ciliary body are replaced by single structure resembling a stunted iris
  • zonular fibers reach up between posterior surface and lens
  • histologically, the structure present does not resemble iris or ciliary body, with stromal and epithelial parts are compact, and structure lacks secretory apparatus, fenestrated capillaries, and musculature of the normal ciliary body
• abnormal cornea morphology (MGI Ref ID J:6131)
  • about 40% exhibit uni- or bilateral corneal irregularities that include depressions or blisters in the cornea
  • exhibit a persistent central stalk-like connection between the lens and cornea; stalk consists of epithelial cells continuous with the subcapsular lens epithelium
  • the persistent stalk connection distorts the curvature of the cornea and the anterior face of the lens
  • the cornea is not well defined at E13
  • stratification of cornea is less pronounced than in wild-type
• abnormal corneal endothelium morphology (MGI Ref ID J:119940)
  • endothelium does not develop normally
  • inner corneal surface is covered by crowded and disorganized layer of cells resembling stromal cells of fused iris/ciliary body
  • there is a high melanosome content in corneal endothelium; these often adhere to the 'iris/ciliary body stroma'
  • mutants show high levels of N-cadherin in all mesenchyme facing the anterior chamber, while in wild-type it is seen in iris epithelium in minute amounts
• abnormal corneal epithelium morphology (MGI Ref ID J:6131)
  • the corneal epithelium is interrupted in the region where the persistent connection between the lens and the corneal epithelium occurs
• abnormal corneal stroma morphology (MGI Ref ID J:76605)
  • corneal swelling associated with a lax, cavernous structure of the stroma is a source of leucoma
  • mild dysplasia of the corneal stroma
  • stroma shows a reduction in number and density of collagen fibers
• corneal opacity (MGI Ref ID J:6131)
  • varying degrees of corneal opacity, ranging from a few tiny spots in the papillary area to a completely opaque central cornea
  • minor central leucoma
• corneal vascularization (MGI Ref ID J:6131)
  • seen in older mutants
• abnormal iridocorneal angle (MGI Ref ID J:119940)
  • filtration angle is severely malformed and ruptures in the tissue frequently occur, while in most sections, it is missing
• abnormal canal of Schlemm morphology (MGI Ref ID J:119940)
• absent trabecular meshwork (MGI Ref ID J:119940)
  • filtration angle is without a trabecular meshwork
• abnormal iris morphology (MGI Ref ID J:6131)
  • iris shows adhesive attachment with the lens
  • iris and ciliary body are replaced by single structure resembling a stunted iris
  • anterior surface of structure is made up of stromal cells; histologically it does not resemble iris or ciliary body, with stromal and epithelial parts are compact and homogeneous lacking muscle cells, blood vessels, nerves and channels in extracellular space like a normal iris
• small pupils (MGI Ref ID J:6131)
• abnormal lens morphology (MGI Ref ID J:6131)
  • lens is irregularly shaped
  • exhibit a persistent connection between the lens and the corneal epithelium
  • at E16, part of the lens protrudes to the exterior and eventually materials from the lens interior are expelled
  • extrusion of lens crystalline materials through the stalk, resulting in a reduced and malformed lens
• abnormal lens development (MGI Ref ID J:76605)
  • exhibit a persistent central stalk-like connection between the lens and cornea
  • the lens fails to separate from the cranial ectoderm at E12
• abnormal lens fiber morphology (MGI Ref ID J:6131)
  • some fibrous structures are found in the lens but they are very disorganized and interspersed by large irregular vacuoles
  • the lens epithelium fails to proliferate leading to a reduction in the number of secondary lens fibers
  • in the E13 lens, the cortical fibers appear less elongated and less regularly aligned
  • appearance of vacuoles in the lens nucleus and cortex marks the beginning of degeneration of fibers
• abnormal lens vesicle development (MGI Ref ID J:6131)
  • the lens vesicle fails to separate from the ectoderm at E10
  • the lens vesicle fails to close which in some cases leads to lens material being ejected to the exterior
  • at E11, the margin of the lens vesicle pit remains open
  • reduction in lens vesicle tissue volume is similar to that observed in Foxe3^dyl homozygotes, while in Foxe3-heterozygotes volume reduction is intermediate between homozygotes and wild-type
• fused cornea and lens (MGI Ref ID J:76605)
  • in some mutants, the anterior surface of the lens and the posterior surface of the cornea adhere directly to each other without a connecting stalk
  • lens vesicle fails to separate from the ectoderm, causing a fusion between the lens and cornea
  • mice show fusion between cornea and small cataractic lens resulting from failure of lens vesicle to close and separate from surface ectoderm
  • in adults, connection may be broken, leaving on central part of external corneal surface a deposit of tissue derived from interior of lens vesicle
• abnormal lens epithelium morphology (MGI Ref ID J:59880)
  • the lens epithelial layer forms during lens vesicle polarization but then gradually disappears and is absent by the time of birth
  • the posterior cells of the epithelium fail to divide and show signs of premature differentiation and the most anterior cells are eliminated by apoptosis
• cataracts (MGI Ref ID J:59880)
  • lens appears cataractous at E16
  • clusters of disorganized cells underneath the lens capsule may cause local cataracts
  • in the E16 lens, vacuoles appear all over the cortex and nucleus as a result of cataractous degeneration
• small lens (MGI Ref ID J:59880)
  • smaller lenses are seen by E13
• abnormal pupillary reflex (MGI Ref ID J:6131)
  • pupillary reaction is absent
• microphthalmia (MGI Ref ID J:6131)
  • small size of the eye varies between individuals and also sometimes between the two eyes of the same individual
• behavior/neurological phenotype
• abnormal pupillary reflex (MGI Ref ID J:6131)
  • pupillary reaction is absent

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Foxe3^dyl related

Mouse/Human Gene Homologs
Peters' Anomaly disease

Sensorineural Research
Cataracts (cortical)
Eye Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Foxe3dyl
Allele Name		dysgenetic lens
Allele Type		Spontaneous
Common Name(s)		dyl;
Strain of Origin		BALB/cLiA
Gene Symbol and Name		Foxe3, forkhead box E3
Chromosome		4
Gene Common Name(s)		ASMD; FKHL12; FREAC8; HFH7; HNF3; dyl; dysgenetic lens;
Molecular Note		Two missense mutations in the sequences encoding the forkhead domain were shown to cosegregate with the dyl phenotype: two C to T transitions at positions 277 and 293 that change codons 93 and 98 from phenylalanine to leucine and serine respectively. These mutations are in a region of the protein thought to be critical for DNA binding. [MGI Ref ID J:59880]

Genotyping

Genotyping Information

This strain will not have a genotyping protocol or one is not currently available.

Helpful Links

Optimizing PCR Protocols

References

References

Additional References

Brownell I; Dirksen M; Jamrich M. 2000. Forkhead Foxe3 maps to the dysgenetic lens locus and is critical in lens development and differentiation. Genesis 27(2):81-93. [PubMed: 10890982]  [MGI Ref ID J:63706]

Ormestad M; Blixt A; Churchill A; Martinsson T; Enerback S; Carlsson P. 2002. Foxe3 haploinsufficiency in mice: a model for Peters' anomaly. Invest Ophthalmol Vis Sci 43(5):1350-7. [PubMed: 11980846]  [MGI Ref ID J:76605]

Sanyal S; Hawkins RK. 1979. Dysgenetic lens (dyl)--a new gene in the mouse. Invest Ophthalmol Vis Sci 18(6):642-5. [PubMed: 109409]  [MGI Ref ID J:6131]

Semina EV; Brownell I; Mintz-Hittner HA; Murray JC; Jamrich M. 2001. Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet 10(3):231-6. [PubMed: 11159941]  [MGI Ref ID J:67172]

Foxe3^dyl related

Blixt A; Landgren H; Johansson BR; Carlsson P. 2007. Foxe3 is required for morphogenesis and differentiation of the anterior segment of the eye and is sensitive to Pax6 gene dosage. Dev Biol 302(1):218-29. [PubMed: 17064680]  [MGI Ref ID J:119940]

Blixt A; Mahlapuu M; Aitola M; Pelto-Huikko M; Enerback S; Carlsson P. 2000. A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev 14(2):245-54. [PubMed: 10652278]  [MGI Ref ID J:59880]

Brahma SK; Sanyal S. 1984. Immunohistochemical studies of lens crystallins in the dysgenetic lens (dyl) mutant mice. Exp Eye Res 38(3):305-11. [PubMed: 6373332]  [MGI Ref ID J:7448]

Brownell I; Dirksen M; Jamrich M. 2000. Forkhead Foxe3 maps to the dysgenetic lens locus and is critical in lens development and differentiation. Genesis 27(2):81-93. [PubMed: 10890982]  [MGI Ref ID J:63706]

Ormestad M; Blixt A; Churchill A; Martinsson T; Enerback S; Carlsson P. 2002. Foxe3 haploinsufficiency in mice: a model for Peters' anomaly. Invest Ophthalmol Vis Sci 43(5):1350-7. [PubMed: 11980846]  [MGI Ref ID J:76605]

Sanyal S; Hawkins RK. 1979. Dysgenetic lens (dyl)--a new gene in the mouse. Invest Ophthalmol Vis Sci 18(6):642-5. [PubMed: 109409]  [MGI Ref ID J:6131]

Sanyal S; Van Nie R; De Moes J; Hawkins RK. 1986. Map position of dysgenetic lens (dyl) locus on chromosome 4 in the mouse. Genet Res 48(3):199-200. [PubMed: 3569904]  [MGI Ref ID J:8673]

Yoshimoto A; Saigou Y; Higashi Y; Kondoh H. 2005. Regulation of ocular lens development by Smad-interacting protein 1 involving Foxe3 activation. Development 132(20):4437-48. [PubMed: 16162653]  [MGI Ref ID J:101730]

Health & husbandry

Health & Colony Maintenance Information

Currently there no information available for this strain. This may be due to the supply level of this strain.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. Genomic DNA is available for this strain from the Mouse DNA Resource.

General Terms and Conditions

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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