SJCRH Logo The human brain as well as visual system is apparently benefiting from the Six3 gene. According to a groundbreaking research triggered by the St. Jude Children’s Research Hospital, the Six3 gene protects future retina by keeping it in a region where the eye is forming, free of signaling protein that can possibly hamper the process. Novel therapies can be introduced for restoring vision lost to the retinal degeneration associated with glaucoma, diabetic retinopathy and age-related macular degeneration.

Previous investigations have suggested that the most important role of Six3 is during the development of nervous system as a regulator of Wnt family for signaling proteins. Retina is known to be a multilayered structure lining the back of the eye. It consists of light-sensing cells and the lens, both of which are essential for vision. Like some animals humans are probably unable to make new cells for replacing those in the retina that are lost because of age or illnesses like macular degeneration or glaucoma.

Guillermo Oliver, Ph.D., member of the St. Jude Department of Genetics and senior author of research, alleged, “Our work suggests that Six3 evolved as a direct regulator of different members of the critical Wnt signaling pathway,” Oliver said. The family of Wnt proteins influences the fate of different cell types by binding to receptors on the cell surface. A few years ago we determined that very early in development Six3 is required for repressing one member of the Wnt family, a gene called Wnt1, to allow proper development of the forebrain. With this new research, we show that a few hours later Six3 is called on again, this time to repress a different Wnt family member, Wnt8b, so formation of the retina can begin.”

In order to ascertain precise therapies for correcting vision or treating blindness, scientists may require data of genes and molecular mechanisms that are involved in normal retinal development. During the research, investigators pointed out that when Six3 was switched off at a key point in mouse embryonic development the retina may not take place. It was also discovered that retinal pigmented epithelium was considerably unaffected by the gene’s absence. This epithelium is assumed to be a cell layer outside the retina that generally provides nourishment to retina cells.

Oliver highlighted, “Our results conclusively demonstrated that for retinal formation to begin, the embryonic forebrain must be Wnt8b free. So the first step in the process is for Six3 to bind to and repress Wnt8b so its expression remains restricted inside its normal boundaries.Our findings provide a molecular framework to the developmental program leading to retina differentiation. The work may also be relevant for devising novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation. We are focused on a very narrow window of time when specification takes place. We need to identify the critical genes that appear in that timeframe.”

Researchers aimed to unfold a direct link between retina deficiency and abnormal expansion of Wnt8b expression into a region where the forebrain normally develops. This region of the developing anterior brain is believed to be where cells undergo a process called specification. After specification these cells seemingly differ and become highly specialized cells of the retina and eye. It was noted that the Six3 protein binds directly to regulatory regions of Wnt8b.

The research was published in the September 20 online edition of the Journal of Clinical Investigation.