June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Role of Tbr2-Irx1 transcription cascade in the development of ipRGC subtypes
Author Affiliations & Notes
  • Takae Kiyama
    Ophthalmology and Visual Science, The University of Texas Health Science Center at Houston, Houston, Texas, United States
  • Ching-Kang Jason Chen
    Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States
  • Dan Su
    Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa, United States
  • Steven Eliason
    Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa, United States
  • Brad Amendt
    Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa, United States
  • Chai-An Mao
    Ophthalmology and Visual Science, The University of Texas Health Science Center at Houston, Houston, Texas, United States
  • Footnotes
    Commercial Relationships   Takae Kiyama None; Ching-Kang Chen None; Dan Su None; Steven Eliason None; Brad Amendt None; Chai-An Mao None
  • Footnotes
    Support  NIH EY024376 (C.A.M), P30EY028102 (UTHealth) , NIH EY032898 (C.K.C), NIH EY034219 (C.K.C), NIH 1RO1 DE028527 (B.A.A), NIH 1R01DE026433 (B.A.A) , NIH T90 DE023520 (B.A.A)
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3623. doi:
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    • Get Citation

      Takae Kiyama, Ching-Kang Jason Chen, Dan Su, Steven Eliason, Brad Amendt, Chai-An Mao; Role of Tbr2-Irx1 transcription cascade in the development of ipRGC subtypes. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3623.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We have previously shown that T-box transcription factor T-brain 2 (Tbr2) is essential for the formation and maintenance of all ipRGCs, and Tbr2-expressing RGCs are indeed ipRGCs. However, it is unclear how the diverse ipRGC subtypes arise from Tbr2-expressing cells during development. To understand how Tbr2-mediated genetic network regulates ipRGC subtype formation, we used an integrated strategy by combining genomics, mouse genetics, and electrophysiological approaches to address this question. Here, we describe a Tbr2-Irx1 transcriptional cascade essential for the development of a subset of ipRGCs.

Methods : We conducted RNA-seq on embryonic day 15.5 wild type and Tbr2-deleted retinas, and compared transcriptome profiles between them to uncover Tbr2-dependent genes. Among the down-regulated genes found in Tbr2-mutant retinas, this study focuses on elucidating the role of Iroquois related homeobox 1 (Irx1) in ipRGC subtype development. To analyze the function of Irx1 in ipRGC development, we generated Irx1LacZ and Irx1flox mouse lines for conditional knockout studies. To characterize the types of Irx1-expressing cells, we generated an Irx1CreERT2 mouse line in which CreERT2 is expressed under the control of Irx1, and paired this line with Ai9 and RosaiAP reporters for electrophysiological recording, developmental and dendritic morphological studies, and central projection analysis.

Results : RNA-seq analysis revealed Irx1 expression is dependent on Tbr2. By in situ hybridization and qRT-PCR, we confirmed that Irx1 expression is significantly down-regulated in Tbr2-mutant retinas, placing Irx1 as a downstream effector of Tbr2. In Irx1 mutant retina, the number of Opn4-expressing cells was reduced in the dorsal retina during development. Genetic sparse labeling and recording uncovered Irx1-expressing RGCs are specific ipRGC subtypes.

Conclusions : We identify Irx1 as a downstream target of Tbr2 during ipRGC development. Irx1 is expressed in a subset of ipRGCs and plays a role in the formation of these cells. We will conduct detailed investigation into the roles of Tbr2-Irx1 transcription cascade in ipRGC development and functions.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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