One of the most interesting, yet poorly understood, developmental processes is that of organ formation. Such complex development requires the coordination of cell growth, differentiation and cell-cell communication. The eye has been a particular favorite for such studies over the past century, however there are many aspects of its development that remain unknown. Through the work of multiple labs, the Pax6 transcription factor has been shown to control the formation of mouse and human eyes. In both of these species, one mutation in Pax6 causes aniridia in humans and a nearly identical condition in mice (called Small eye). When both copies of Pax6 are missing or abnormal, the eye completely fails to form. Despite these findings, the role of Pax6 at the molecular level remains unclear. For instance, does Pax6 control eye formation by regulating many different types of genes or only a few genes (which themselves regulate a few or many genes)? One of the best way to study how transcription factors function is to identify where they bind and what genes they activate or regulate. However, very few of these “targets” have been identified for Pax6. I identified two genes, Hes1 and Ath5, which are regulated by Pax6 and are basic helix-loop-helix transcription factors involved in neuron formation. These studies linked Pax6 regulation to the process of retinal neural development for the first time.
Although Hes1 and Ath5 require Pax6 for their expression, it is unclear if they are direct transcriptional targets or other genes act as intermediaries between them and Pax6. My laboratory is investigating the molecular mechanism of Pax6 regulation of Ath5 and Hes1, by searching for eye-specific enhancers in Ath5 and Hes1 regulatory regions and testing Pax6 binding. A second project is a functional study of Ath5 during retinal development. We have discovered that mice, who lack functional Ath5, fail to form optic nerves and have profoundly abnormal retinal neuron differentiation. Future work will explore the underlying cause of this deformity in these mice. Similar to mutations in Pax6, the lack of an optic nerve in Ath5 mutant mice is nearly identical to a condition called optic nerve aplasia. We hope to identify children with this condition and investigate whether their Ath5 gene is abnormal. In the future, we hope to investigate how and why Hes1 mutant mice have smaller than normal eyes and if this condition may correlate with a human ocular disease.