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Sabine Fuhrmann, Mary P. Colasanto, Charles Murtaugh, Elizabeth J. Bankhead; Effect Of Tissue-specific Disruption Of Porcupine On Mouse Eye Development. Invest. Ophthalmol. Vis. Sci. 2011;52(14):912.
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During fetal development, the formation of the neural retina, retinal pigment epithelium (RPE) and anterior eye segment require highly coordinated tissue-tissue interactions and complex patterning events. The molecular signals that mediate these processes are not well understood. Excellent candidate signals are the Wnt ligands that control key processes during development and disease such as proliferation, cell fate decisions, tissue polarity and regeneration. The O-acyltransferase Porcupine (Porcn) is required for posttranslational modification regulating secretion and signaling activity of Wnts. PORCN deficiency in humans causes Focal Dermal Hypoplasia (FDH, Goltz Syndrome), an X-linked dominant multisystem birth defect that is frequently accompanied with ocular abnormalities resulting in coloboma, microphthalmia or, in severe cases, in anophthalmia. To gain insight into the contribution of canonical and non-canonical Wnt signaling during eye development, we are conditionally disrupting the Porcn gene in mouse.
The conditional Porcn allele was generated by inserting loxP sites flanking exons 2-3. Thus, Cre-mediated recombination eliminates the start codon and the first 3 predicted transmembrane domains of the protein, likely producing a null or strong loss-of function allele. Porcn is disrupted in the developing mouse eye using tissue-specific Cre lines, and mutant eyes are analyzed by histological and immunohistochemical techniques.
Eye-specific disruption of Porcn results in defects with variable frequency, such as microphthalmia, coloboma and shortened presumptive ciliary body. Initial immunohistochemical analysis showed that Otx1/2 antibody labeling is detectable in mutant RPE using different ocular Cre lines. However, our preliminary data suggest that retina-specific disruption of Porcn causes transdifferentiation of the dorsal RPE into retina.
Our studies indicate that expression of Porcn is critical for early eye development in mouse. Some of the observed defects are not detected upon interference with canonical Wnt signaling alone suggesting either a novel role for non-canonical Wnt signaling or a Wnt-independent function of Porcn during ocular development.
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