eNews November 11, 2015

ApcMin: intestinal adenomas and nearsightedness?

A link between familial intestinal adenomas and myopia

Familial adenomatous polyposis (FAP) is a heritable condition in which affected individuals develop benign intestinal polyps.  Often, polyps progress to colorectal carcinomas later in life.  Mutations in the Wnt pathway member APC (Adenomatous polyposis coli) gene correlate with FAP and progression to colon tumors.  Studies also have revealed a higher incidence of myopia, or nearsightedness, in FAP individuals compared with the incidence in the general, aging population.   In a recent PLoS One article, researchers led by Dr. Zuguo Liu at Xiamen University used C57BL/6J-ApcMin/J (002020) mutant mice to investigate the mechanistic link between a known polyp susceptibility mutation and ocular degenerative phenotypes.  Their data demonstrate that eyes in affected ApcMin mice harbor morphological alterations that resemble changes that contribute to abnormal ocular refraction in humans.  Their data suggest that C57BL/6J-ApcMin/J mice may be a useful model to study myopia as well as intestinal adenomas.

Ocular organization and refractive index are altered in ApcMin mice

ApcMin is a chemically-induced (ENU) mutation that creates a premature translational stop codon.   The encoded truncated protein cannot perform its usual role in the Wnt signaling pathway, where it helps promote degradation of β-catenin, a transcriptional co-activator.  Without proper APC activity, β-catenin accumulates in the cytoplasm and then translocates into the nucleus where it binds with TCF/LEF transcription factors to regulate the expression of many genes involved in cell proliferation, differentiation, and other pathways.   ApcMin is similar to APC mutations identified in patients with FAP, the majority of which produce truncated, mutant APC proteins, and that lead to defects in Wnt signaling and increased β-catenin-associated transcription.  C57BL/6J-ApcMin/J mice develop numerous spontaneous intestinal adenomas, and are commonly used as a research model for human FAP. 

In order to determine if the ApcMin mutation in mice leads to ocular abnormalities reminiscent of myopic changes observed in FAP patients, Dr. Liu’s team measured several biometric parameters in affected mice at several postnatal ages ranging from P28-P84, examined sclera organization by electron microscopy, and examined expression of key factors that contribute to eye morphology and refraction.  C57BL/6J-ApcMin/J mutant mice were more myopic than wild-type littermates (-4.64 compared to -0.22 diopters respectively), especially at later ages. This difference in ocular refraction in ApcMin mice was accompanied by significant increases in vitreous chamber depth and decreases in the eyes’ axial lengths compared to wild-types, indicating deregulation of eye architecture and alterations in image focusing power.  Histological examination of the retinas in the mice also revealed ruptures in the retinal pigment epithelium in addition to thicker retinas compared to wild-types.  Because ApcMin regulates cell growth and proliferation via the Wnt pathway in intestinal epithelium cells, the researchers also measured cell proliferation in ApcMin retinas by immunohistochemical staining and immunoblots of the proliferation marker Ki67.  In both analyses, increased Ki67 expression was observed in retinal cells from ApcMin mice compared to age-matched wild-type controls.  These observations suggest that abrogation of Apc activity in ApcMin mice leads to increased cellular division, which alters the eye architecture and promotes myopia. 

The Liu team’s data provides new understanding for APC’s role in regulating cellular proliferation in tissues other than intestinal epithelium.  Further, it demonstrates the potential for using C57BL/6J-ApcMin/J mice to model myopia in addition to its already established one for modeling intestinal polyps.  Finally, this model may serve as a useful platform for investigating the molecular regulators that contribute to eye architecture and myopia development.

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