05 Oct Gene Controls What Big Eyes You Have….
MedicalResearch.com Interview with:
Dr. Annabel Christ PhD
Max-Delbrueck-Center for Molecular Medicine
Medical Research: What is the background for this study?
Dr. Christ: The development and function of the retina in all vertebrate species follow the same principles. Still, there is one important feature that distinguishes the mammalian eye from that of others inasmuch as it does not grow much after birth. In contrast, in fish or reptiles, the retina continuously grows, even in adults. The mechanism that restricts the growth of the mammalian eye remains enigmatic. Yet, understanding this mechanism may offer therapeutic strategies to block eye growth in cases of severe nearsightedness or to induce growth of the retina in patients with retina degeneration.
To explore the mechanisms that control human eye growth we studied a genetic form of extreme eye overgrowth (buphthalmia). It is caused by an inherited defect in the gene encoding LRP2, a receptor in the retina. We reasoned that this exceptional form of eye disease might tell us something about the concepts governing eye growth in all humans.
Medical Research: What are the main findings?
Dr. Christ: As an experimental model, we generated strains of mice that carry a genetically engineered defect in the LRP2 gene. Inactivation of the LRP2 gene in mice caused similar eye overgrowth as in patients, validating the usefulness of this animal model for understanding the human condition. Studying the development of mouse eyes in vivo and in retinal explant cultures we elucidated the mechanism that restricts the growth of the retina in mammals. Thus, in the retina, LRP2 blocks the action of a growth factor known as sonic hedgehog (SHH). SHH is an important factor to induce growth and differentiation of the mammalian retina during embryonic development. However, in the late embryonic and post-natal eyes, LRP2 prevents the action of SHH in the tip of the retina to prevent further growth. In more technical terms, LRP2 imposes quiescence on the stem cell niche in the margin of the mammalian retina.
Medical Research: What should clinicians and patients take away from your report?
Dr. Christ: Obviously, inherited gene defects in LRP2 are very rare cases of eye disease. Still, our studies have told us something about the competing action of two key players, SHH and LRP2, in balancing growth of the mammalian eye. Conceivably, more subtle defects in LRP2 activity may also underlie increased eye size in common forms of nearsightedness. Also, means to block LRP2 activity temporarily in the adult eye may provide a therapeutic avenue to re-introduce growth of the retina in individuals with retina degeneration.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: Further studies should be directed towards the development of pharmacological compounds that modulate LRP2 activity. Applied locally in the eye, these compounds may be applicable for the treatment of eye overgrowth but also for regenerative therapies in retina generation.
Annabel Christ et al. LRP2 acts as SHH clearance receptor to protect the retinal margin from mitogenic stimuli. Developmental Cell, October 2015 DOI: 10.1016/j.devcel.2015.09.001
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Dr. Annabel Christ PhD (2015). Gene Controls What Big Eyes You Have….