Peters anomaly is an anterior segment dysgenesis and a leading cause of congenital corneal opacity. Here, we show that loss of ABL kinases restores lens induction in the absence of FGF signaling but induces Peters anomaly type II independently of ERK signaling, a phenotype also observed with elevated FGF-Ras activity. This defect is rescued by allelic deletion of the ABL substrates CRK and CRKL. Contrary to prevailing models, ABL kinases do not act through direct phosphorylation of CRK proteins; instead, they phosphorylate PTPN12, suppressing p130CAS phosphorylation and CRK recruitment required for RHO GTPase activation. ABL kinase deficiency reduces actomyosin contractility in the lens vesicle and genetically interacts with RHOA inhibition, whereas RAC1 inhibition ameliorates disease phenotypes. These findings define an ABL-PTPN12-p130CAS pathway that controls cytoskeletal tension during lens vesicle separation and suggest that modulation of this process may offer a therapeutic approach for Peters anomaly type II.
Wu et al. (Wed,) studied this question.