Light is an important regulator of circadian biology and behavior. Light-triggered visual functions are orchestrated by multiple channels conveyed and/or conducted by specific retinal ganglion cell (RGC) types. Despite significant progress in our understanding of the morphologies and functions of the twenty-plus RGC types, the genetic and molecular basis underlying the formation and survival of the diverse RGC types remain poorly understood. This grant application focuses on the roles of transcriptional factors Tbr2 and Tbr1 in regulating specific types of retinal ganglion cells (RGCs). Our current understanding is that Tbr2 participates in specifying the fate and maintaining the survival of ipRGCs, and some Tbr2+ RGCs serve as reservoir of ipRGCs. Additionally, Tbr1 marks 2 distinct subsets of RGCs, including OFF direction-selective JAM-B RGCs. The goals of this application are to understand Tbr2-mediated genetic regulatory network for the formation of ipRGCs and to gain comprehensive understanding of Tbr2+ and Tbr1+ RGCs.
Specific Aim 1. a) Test the hypothesis that some Tbr2+ RGCs that have low levels of Opn4 expression can serve as a reservoir for ipRGCs; b) To determine the identity of Spp1+Tbr2+ RGCs and whether Spp1 negatively regulates Opn4 expression.
Specific Aim 2. a) Test the hypothesis that Tbr2 may function as a master regulator of ipRGCs by ectopically expressing Tbr2 in Tbr1+ RGCs; b) Test the combinatorial effect of Tbr2 and Isl1 in regulating ipRGCs.
Specific Aim 3. Test the hypothesis that Tbr1 marks and regulates unique subsets of RGCs: a) Determine the identity of Tbr1+ RGC types; b) Determine the functions of Tbr1+ RGCs; and c) Investigate the roles of Pou4f1 in regulating Tbr1+ RGCs. The objective of this application-to obtain integrative knowledge regarding RGC subtypes (transcription regulation, morphologies, central projections, and physiological functions)-is important to understand the molecular mechanisms underlying RGC subtype formation, and the structure and function of retinal circuits. It is also in line with the specific research interest described in the recently announced NEI Audacious Goal Initiative (://grants.nih.gov/grants/guide/rfa-files/RFA-EY-14- 001.html).
In a mature mammalian retina, more than twenty distinct types of retinal ganglion cells (RGCs), the important components of retinal circuits and functions, have been described on the basis of their morphologies and functions. By learning how RGC subtypes are regulated by T-box transcription factors Tbr1 and Tbr2, we will obtain new information on the fundamental principles guiding retinal ganglion cell development and why they die under certain disease conditions, such as glaucoma and ischemic optic neuropathy. Such knowledge is important to develop novel therapeutic strategy for retinal stem cell reprogramming.
| Kiyama, Takae; Chen, Ching-Kang; Wang, Steven W et al. (2018) Essential roles of mitochondrial biogenesis regulator Nrf1 in retinal development and homeostasis. Mol Neurodegener 13:56 |
| Mao, Chai-An; Agca, Cavit; Mocko-Strand, Julie A et al. (2016) Substituting mouse transcription factor Pou4f2 with a sea urchin orthologue restores retinal ganglion cell development. Proc Biol Sci 283:20152978 |
| Martin, David; Kim, Yung-Hae; Sever, Dror et al. (2015) REST represses a subset of the pancreatic endocrine differentiation program. Dev Biol 405:316-27 |
