Meis1 and Meis2 are jointly required for advanced stages of mouse lens morphogenesis

The TALE homeodomain transcription factors Meis1 and Meis2 are broadly co-expressed during vertebrate organogenesis. They serve as critical regulators of early mouse lens morphogenesis at the lens placodal stage; however, their cooperative roles in subsequent lens morphogenesis remain unknown. Using a BAC-derived Foxe3 -Cre driver active in proliferating anterior lens epithelium from embryonic stage E10.5, we conditionally ablated Meis1 and Meis2 individually and in combination and analyzed ocular development from E11.5 to postnatal day P21. Double mutants exhibited early-onset lens hypoplasia and epithelial disorganization detectable by E12.5, progressing to striking postnatal phenotypes characterized by small, highly vacuolated, triangular lenses that frequently detached and floated within malformed anterior segments. At mid-gestation, double mutants showed elevated apoptosis in the emerging lens epithelium and aberrant cell-cycle activity within primary fiber cells. Furthermore, levels of Pax6, FoxE3, Prox1, and Sox1 proteins in lens epithelium were reduced, while Sox2 was ectopically expressed. Junctional and epithelial integrity defects included central loss of ZO-1 and induction of α-smooth muscle actin, while N-cadherin levels were largely unchanged. Anterior segment abnormalities encompassed absence of the anterior chamber and iris–cornea adhesions. By contrast, Meis1 -only mutants displayed variable lens and anterior segment defects, including a “big eye” phenotype with optic nerve and retinal ganglion cell abnormalities, whereas Meis2 -only mutants were largely normal. These findings identify stage-selective, cooperative functions of Meis1 and Meis2 that maintain Pax6 expression, epithelial integrity, and growth, revealing novel Meis1/2 - dependent pathways that are essential for advanced lens morphogenesis.