TABLE 2.

EphA2 and ephrin-A5 knockouts and mutations in mice.

EphA2 −/− genetic background	Knock-out/-in strategy	Phenotype (age)	Cellular changes	Potential cause for cataracts	References
129/SvJ:C57BL/6J	Secretory gene trapping (intron 1)	Cortical cataracts progressing to involve the whole lens and lens rupture (not provided)			Jun et al. (2009)
FVB/NJ	Secretory gene trapping (between exon 5 and intron 6)	Cortical cataracts (3 months) progressing to involve the whole lens (6 months) and finally lens rupture (8 months)	Clusters of cortical vacuoles (1 month), upregulation of Hsp25 protein	Cellular stress and protein misfolding	Jun et al. (2009)
Mixed FVB:C57BL6J	Secretory gene trapping (between exon 5 and intron 6)	Mild anterior cortical lens opacity (11 weeks); severe anterior cortical opacities (18 weeks)			Dave et al. (2021)
C57BL/6J	Secretory gene trapping (between exon 5 and intron 6)	Mild anterior cortical lens opacity (11 weeks); severe anterior cortical opacities (38 weeks)	Disorganized, irregularly shaped and swollen fiber cell and lens epithelium have vacuoles	Fiber cell disorganization	Dave et al. (2021)
C57BL/6J	Insertion of vector in exon 5	Mild nuclear cataract (P21), disrupted gradient refractive index (8 weeks) and increased resilience (8 weeks)	Misaligned meridional equatorial epithelial cells and lens fulcrum, disorganized fiber cells, disrupted suture apex centration and abnormal fiber cell membrane conductance	Abnormal nuclear fiber morphology and compaction	Cheng and Gong (2011), Cheng et al. (2013), Cheng et al. (2017), Cheng (2021), Cheng et al. (2021), Cheng et al. (2022)
C57BL/6J	Insertion of vector in exon 5	Smaller spherical lenses (2+ weeks) with reduced refractive power of the outer lens layers	Disorganized fiber cells, disturbed lens gradient index, and suture misalignment	Disrupted migration of fiber cells	Shi et al. (2012)
C57BL/6J	Insertion of vector in exon 5	Small lens with degraded optical quality (P21)	Decreased proliferation of lens epithelial cells, misaligned fiber cells with disturbed suture formation	Defective early patterning in cell differentiation contribute to later defects in patterning	Zhou and Shiels, (2018)

Ephrin-A5 mutant genetic background	Knock-out/-in strategy	Phenotype (Age)	Cellular changes	Potential cause for cataracts	References
EphA2-R722Q C57BL/6J	CRISPR/Cas9 gene editing	No obvious cataracts (P21–12 months)	Longer/unequal posterior suture branches at P30	Patterning defects due to the disruption of cytoskeleton-associated protein expression	Zhou et al. (2021)
EphA2-del722 C57BL/6J	CRISPR/Cas9 gene editing	Translucent regions (P21–12 months)	Disrupted meridional epithelial-to-fiber cell alignment at the equator, deviated polar axis at the posterior pole with severe suture defects, misaligned hexagonal fiber cell radial columns, and retention of EphA2 in the cytoplasm	Patterning defects in the epithelial and fiber cells and disruption of cytoskeleton-associated protein expression	Zhou et al. (2021)

Ephrin-A5 −/− genetic background	Knockout strategy	Phenotype (Age)	Cellular changes	Potential cause for cataracts	References
Mixed 129/Sv:C57BL/6	Insertion of vector in exon	Progressive cortical cataracts with rupture of the posterior lens capsule (2 months)	Disorganized and rounded fiber cells	Loss of cell-cell adhesion due to loss of N-cadherin from the cytoplasmic membrane	Cooper et al. (2008)
Mixed 129/Sv:C57BL/6	Insertion of vector in exon	Nuclear cataract (P21)	Presence of large vacuoles in the equatorial region, severe fiber cell degeneration, and lens rupture	Affected fiber cell packing during epithelial cell differentiation	Son et al. (2013)
Mixed 129/Sv:C57BL/6	Insertion of vector in exon	Nuclear cataracts (2 months) followed by posterior capsule rupture	Disruption of N-cadherin-β-catenin complex that affects the interlocking protrusions causing cataract	Presence of membranous globules along the fiber cells disrupted interlocking protrusions in fiber cells	Biswas et al. (2016)
C57BL/6J	Insertion of vector in exon	Anterior polar cataracts (P21), mild decrease in maximum refractive index (8 weeks) and increased resilience (8 weeks)	Disruption of cell-cell adhesion (E-cadherin and β-catenin) in anterior epithelial cells leading to abnormal proliferation, disorganized suture apex centration and abnormal fiber cell membrane conductance	Aberrant EMT in anterior epithelial cells invading underlying fiber cells	Cheng and Gong (2011), Cheng et al. (2017), Cheng (2021), Cheng et al. (2021), Cheng et al. (2022)
C57BL/6J	Insertion of vector in exon	Small lens with degraded optical quality (P21)	Disturbed epithelial meridional pattern, radial fiber cell pattern, and suture disorganization	Defective early patterning in cell differentiation contributes to later defects in patterning	Zhou and Shiels, (2018)

EphA2 −/− ephrin-A5 −/− double knockout genetic background	Knockout strategy	Phenotype (Age)	Cellular changes	Potential cause for cataracts	References
C57BL/6J	Insertion of vector in exon	Mild nuclear cataract (P21) and anterior polar cataract (P21) (additive phenotype from each single knockout)	Misaligned meridional equatorial epithelial cells and disorganized fiber cells and aberrant proliferation of anterior epithelial cells	Fiber cell disruptions and aberrant EMT in anterior epithelial cells	Cheng et al. (2017)