Genetic dissection of Pax6 dosage requirements in the developing mouse eye

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Abstract
Haploinsufficiency of the transcription factor Pax6/PAX6 has been implicated in a number of congenital eye disorders in humans and mice, such as aniridia and Small-eye, which affect the development and function of the lens, cornea, anterior eye segment and neuroretina. However, the widespread distribution of Pax6/PAX6 protein within the developing and adult eye preclude the identification and direct study of the ocular tissues affected by a reduction in Pax6/PAX6 dosage. Here, we employed Cre/loxP-mediated inactivation of a single Pax6 allele in either the lens/cornea or the distal optic cup to dissect the tissue-specific sensitivity to Pax6 haploinsufficiency. Exclusive inactivation of a single Pax6 allele in the lens recapitulates the Small-eye lens and corneal defects, while only mildly affects iris morphology in a non-cell-autonomous fashion. Conversely, selective inactivation of a single Pax6 allele in the distal optic cup revealed primarily cell-autonomous dosage requirements for proper iris differentiation, with no affects on either lens or corneal morphology. Pax6 dosage within the distal optic cup is found here to influence the number of progenitors destined for the anterior ocular structures, the timing of iris muscle-cell differentiation and iris stroma development. Taken together, we genetically dissected the complex mouse Small-eye phenotype, thereby pinpointing the underlying Pax6/PAX6 haploinsufficiency to autonomous dosage requirements within the developing iris and lens/cornea tissues.