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Sexual dimorphism shapes AAK trajectory in Pax6 deficiency mouse model with early immune activation, impaired innervation, and altered tears

ABSTRACT: Congenital aniridia often progresses to vision-threatening aniridia-associated keratopathy (AAK), yet when and how reduced PAX6 dosage destabilizes the ocular surface has remained unclear. Here we combine a conditional Pax6 haploinsufficient mouse with whole-mount imaging, functional assays, and sex-stratified corneal transcriptomics and tear-film proteomics to build an integrated, systems-level picture of disease initiation and progression. Pax6+/− pups show delayed eyelid opening, and from the moment of first environmental exposure the cornea is primed for pathology: leukocytes accumulate by postnatal week two and remain elevated thereafter, epithelial differentiation is mis-specified (KRT12 loss with central expansion of KRT14), and central proliferation is persistently depressed despite grossly normal wound closure. Sensory architecture and function are profoundly impaired, fine epithelial fibers and TRPM8+ terminals are depleted, and corneal sensitivity is reduced, while trigeminal ganglion transcriptomes change little, pointing to a cornea-intrinsic guidance/maintenance failure. Sex emerges as a potent modifier: in otherwise modestly dimorphic wild-type corneas, Pax6 haploinsufficiency drives male- and female-specific gene networks that converge on inflammation and extracellular-matrix remodeling but diverge in metabolic and innate-immune programs; tears mirror and likely reinforce these shifts, with female-biased hyposecretion at baseline and, after abrasion, a failure of Pax6+/− tears to mount the ribosome/translation and axon-guidance response seen in controls, instead exaggerating innate-immune and keratinization pathways. Together, the data recast AAK as a vicious cycle of epithelial dysmaturation, chronic inflammation, and neurotrophic failure amplified by sex-modulated lacrimal changes. By pinpointing early inflammatory priming, a cornea-encoded denervation mechanism, and modifiable tear-film deficits, this work nominates tractable entry points, tempering inflammation, restoring neurotrophic support and reinnervation, and normalizing tear quality, with direct translational relevance to preventing or slowing AAK.

ORGANISM(S): Mus musculus

PROVIDER: GSE326648 | GEO | 2026/05/27

REPOSITORIES: GEO

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Project description:PAX6-related Aniridia is a sight-threatening disease due to progression of secondary glaucoma and aniridia associated keratopathy (AAK). Changes or loss of limbal epithelial progenitors causes the epithelial surfaces defects. We analyzed how PAX6 contribute to this with a two-step approach. 1) mRNA Sequencing of limbal epithelial cells isolated from controls and aniridia patients. 2) confirming the bioinformatical and literature-based result list on a siRNA based primary aniridia cell model (PAX6- knockdown). With this approach genes which are directly influenced by PAX6 should be distinguishable from genes secondary affected by AAK disease state. Therefore epithelial cells were isolated from the limbus region of two patients with aniridia and cultured in KSFM medium. Normal cells were obtained from limbus region of cadaveric control patients. For the siRNA based anridia cell model cells were transfected with lipofectamine and 5 nM siRNA against PAX6 or scrambled control. All cells were lysed to obtain DNA, RNA and protein. Reduction of PAX6 protein was controlled by Western Blot. Aniridia and Control Poly-A enriched RNA-librarys were subjected to Next Generation Sequencing. The differential analysis was a combination of quantification with RSEM and differential tests with edgeR. Gene lists were filtered by comparing to NCBI GEO Datasets, annotation with DAVID and manually annotation using literature search. For the resulting filtered gene list qPCR primer were ordered and postulated changes were verified with qPCR on siRNA based aniridia- cell model (Namely: TP63, ABCG2, ADH7, ALDH1A1, PITX1, DKK1, DSG1, K12, K3, K13, SPINK6, SPINK7, CTSV, SPERPINB1). We could identify genes which might be regulated by PAX6. We could show that SPINK7 mRNA coding for a protease inhibitor is downregulated in patients as well as in our primary aniridia cell model. ALDH1A1 and AHD7 mRNAs were reduced in limbal epithelial cells of aniridia patients (AN-LEC). Both transcripts were downregulated upon PAX6 knockdown in our cell model.Our siRNA-based aniridia cell model is a tool to proof identified PAX6 affected genes which might drive AAK pathogenesis. We could demonstrate, that this is the fact for transcripts coding for retinol converting enzymes. This provides evidence that PAX6 might drive corneal epithelial differentiation process by direct or indirect controlling retinoic acid signaling processes.

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Sexual dimorphism shapes AAK trajectory in Pax6 deficiency mouse model with early immune activation, impaired innervation, and altered tears

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