Dissecting the role of LIM -homeobox gene LMX1B in the development of the ocular anterior segment

Malformation or improper function of anterior segment (AS) tissues contributes to many ocular diseases, including glaucoma, a complex blinding disease that is often associated with elevated intraocular pressure (IOP). Haploinsufficiency of the LIM-homeobox gene LMX1B raises the risks of glaucoma and ocular hypertension. The mouse ortholog of LMX1B is expressed in the periocular mesenchyme. Targeted disruption of Lmx1b leads to AS dysgenesis, linking Lmx1b to ocular development and pathogenesis of glaucoma. However, complete loss of Lmx1b cannot be used to determine the requirement of Lmx1b in specific cell lineages, and neonatal lethality prohibits further investigation of Lmx1b function in the adult eye. ^ By studying conditionally engineered Lmx1b mutant mice, I defined the spatial and temporal roles of Lmx1b in ocular development and in the adult eye. We show that Lmx1b is predominantly expressed in the neural crest (NC) component of the periocular mesenchyme. NC-specific knockout of Lmx1b led to ocular defects identical to those of homozygous null mutants, indicating the intrinsic role of Lmx1b in the NC to direct the specification of corneal stroma, presumptive iris stroma and ciliary body. Mice with NC-specific deletion of Lmx1bwere not viable. To determine the requirement of Lmx1b in the postnatal ocular development, we generated periocular mesenchyme-specific Lmx1b knockout mice and demonstrate that Lmx1b is also required for the formation of corneal endothelium and aqueous drainage tissues, e.g. trahecular meshwork (TM) and Schlemm\u27s canal, that are important for regulating IOP. In adult eye, Lmx1b is crucial to maintain the transparency of the cornea and regulate extracellular matrix organization in the corneal stroma. To further address the function of Lmx1b specifically in mature TM, we established an inductive system that could be used to selectively delete Lmx1b in this tissue. Additionally, analysis of a dominant-negative allele of Lmx1b establishes that development of different organs requires Lmx1b in a dosage-sensitive manner. These data demonstrate essential roles of Lmx1b in both pre- and postnatal development of AS and requirement of Lmx1b for the maintenance of adult ocular function. This enriches our understanding of the etiology of glaucoma associated with LMX1B mutations.