bHLH Factor Math5/Atoh7 Regulates RGC Neurogenesis
Mouse retinal neurogenesis initiates at early E11 in the central optic cup coincident with the appearance of Math5/Atoh7 (Top panels, Figure 1). Atoh7 (Drosophila atonal orthologue) encodes a transcription factor with a bHLH domain. Atoh7 is expressed by retinal progenitors, not mature RGC neurons. Previously, we created a targeted deletion of Atoh7 that causes the complete loss of RGCs, optic nerves and chiasmata (Figure 2) and an increase in cone photoreceptors (Bottom panels in Figure 1).
Besides investigating the retinal phenotypes of Atoh7 mutant mice, we have created two tools for studying cells that express the Atoh7 gene product. First, we inserted the bacterial LacZ gene into the Atoh7 locus in a targeted deletion experiment. This allows us to visualize retinal cells that express, or did express, Atoh7 (Figure 1). More recently we have made transgenic mice that contain Atoh7 regulatory regions driving the expression of the jellyfish protein GFP (Figure 3). Both the LacZ and GFP reporters persist long enough during retinal development to mark the RGC axons growing into the forming optic nerve lumen and onwards to the brain.
In addition to understanding how Atoh7 functions during RGC genesis, we are investigating what genes turn Atoh7 on and off at the right time and place. One obvious candidate to activate retinal bHLH factors is the transcription factor Pax6. All developing eye cells express Pax6 at some stage, and the removal of Pax6 function causes a complete failure of eye development. Using Math5-GFP transgenic mice, we recently defined a 5' cis regulatory element that activates Math5/Atoh7 transcription during embryonic retinal development (Figure 3). We also found that Pax6 directly binds to DNA within this element.
However, Pax6 cannot be the sole regulator of Math5/Atoh7, since optic cup cells uniformly express Pax6 at the time when Atoh7 expression is highly patterned. We previously demonstrated that Hes1 temporally represses the expression of Atoh7 until the stage when retinal neurogenesis begins. Very recent work in the lab has shown that Hes1 repression of Atoh7 and retinal ganglion cell formation occurs in response to Notch signaling. Currently we are investigating some of the many roles that the Notch pathway performs during embryonic retinal development, and the molecular mechanism by which this pathway regulates Math5/Atoh7 expression.
Contact Us
The Brown laboratory is part of the Division of Developmental Biology and the Department of Ophthalmology at Cincinnati Children's Research Foundation and the University of Cincinnati School of Medicine. Our lab is located in Location R (Research Foundation Building), Room 3001.
Our laboratory participates in pre- and post-doctoral training through the Molecular and Developmental Biology and Neuroscience Programs. Inquiries from interested trainees are always welcome.
For more information, please contact Nadean Brown at 513-636-1963 (nadean.brown@cchmc.org).
