Blimp1 Tells Retinal Cells What They’ll Become
By Anna Fimmel
Every little kid knows what they want to be when they grow up. Fireman, ballerina, Batman, truck-driver,…. Unlike little kids, immature retinal cells need someone to tell them what they’re going to be. For example, different homeodomain transcription factors —proteins that bind to specific bits of DNA called homeoboxes – regulate which genes get turned on and off in retinal progenitor cells. It’s a little bit like playing different notes on a guitar. Your fingers are the homeodomain transcription factors, the strings are lengths of DNA, and the exact spots on the guitar fret that correlate with specific notes are homeoboxes, One particular homeodomain transcription factor is called Otx2. It helps retinal progenitor cells to turn into one of two kinds of cells. Otx2-positive cells choose to become either photoreceptors (rods and cones—the cells that detect light and color) or bipolar cells (interneurons that function as go-betweens for photoreceptors and retinal ganglion cells, which convey visual signals to the brain). In their 2010 study, Brezezinski et al. focused specifically on a protein expressed by Otx2+ cells, Blimp1. They hypothesized that the presence of Blimp1 acts as the ‘switch’ that turns a developing retinal cell into a photoreceptor (instead of a bipolar cell). Earlier studies had suggested a link, but the exact mechanisms had never been laid out. To test their hypothesis and to expand on the previous research, the scientists engineered a mouse model that lacked Blimp1 in retinal progenitor cells. Next, they monitored the growth of the conditional knockout mice versus the control mice, and assayed for bipolar cells or photoreceptor cells by detecting the presence or absence of proteins found only in either bipolar or photoreceptor cells. They found that absence of biases progenitor cells towards bipolar cells or, quite surprisingly, Müller glia instead of bipolar cells. Directly mirroring that, there was increased Chx10 expression, confirming the presence of bipolar cells. What’s more, although not as obvious as the increase in bipolar cells, there was also an increase in Müller glia in conditional knockout mice! Unexpected! This increase could be the result of a direct phase shift of Otx2 cells into glia. This was supported by a two-fold increase in both Sox9 (another transcription factor—one whose presence possibly in this case might herald Müller glia cells) and Otx2/Sox9 cells in conditional knockouts at postnatal day 7, suggesting that at least some glia come from Otx2 cells. They also observed the Otx2/Sox9 cells in adult conditional knockout retinas.
This result suggested that Blimp1 acts as a sort of stabilizing agent—like guidance counselors for cells. In this case, an Otx2-positive cell is like a student who wants to be either an art historian (photoreceptor) or a businessman (bipolar cell). He already is leaning towards being an art historian, and his guidance counselor (Blimp1) supports his decision. Had Blimp1 not been his guidance counselor, the student would have coerced by others, like Chx10 and sometimes Sox9. These factors don’t think art is worth anyone’s time or money and encourage the cell to become a businessman. Blimp1 and Chx10 are like switches for photoreceptors and bipolar cells, and both of them require Otx2. More Otx2+ cells expressing Blimp1 would lead to more photoreceptors, and more Otx2+ cells expressing Chx10 would lead to more bipolar cells.
So, to recap: There is a certain subset of retinal cells that have Otx2—a homeodomain transcription factor. A subset of these Otx2+ cells express Blimp1 which, the researchers from this study theorized, is the switch flipped that tells the cell to become a photoreceptor. If, instead of Blimp1, the cell has Chx10, then it will become a bipolar cell or even a Müller glial cell. They tested this by taking away Blimp1 and seeing what would happen. The results supported their hypothesis, but they couldn’t be absolutely sure of a connection until they did more tests.
So the researchers over-expressed Blimp1 and found that it biased cells toward a photoreceptor fate. Back to the ‘student and guidance counselor’ analogy, Blimp1 overexpression would be if the counselor escorted the student to class every day, hovering over his shoulder and telling him to do art history. Following him home. Watching him sleep at night. His parents are definitely starting to worry. Without the presence of the guidance counselor OR the disapproving friends, the hypothetical student will grow up to be neither an art historian nor a businessman…maybe even a scientist.
This sort of research is important for more than just ‘learn about the world’ sort of reasons. Getting more detailed information about how retinal cells are developed leads to a better understanding of and ability to treat retinal disorders. The World Health Organization estimates that 2.6% of the entire population is in some way significantly visually impaired (.6% of the population being totally blind). Disorders like macular degeneration plague people every day, and treatment is expensive, time-consuming, and sometimes painful. Investigating the processes by which the body makes eye cells it needs gets us one step closer to restoring the vision of millions, safely and non-invasively. All in all, it’s easy to see why such research is necessary!
Click here to access the research article on which this piece is based.