Tbr2-dependent parallel pathways regulate the development of distinct ipRGC subtypes

Takae Kiyama; Ching-Kang Chen; Halit Y Altay; Yu-Jiun Chen; Leviette Sigala; Dan Su; Steven Eliason; Brad A Amendt; Chai-An Mao

doi:10.1038/s42003-026-09645-4

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Tbr2-dependent parallel pathways regulate the development of distinct ipRGC subtypes

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Tbr2-dependent parallel pathways regulate the development of distinct ipRGC subtypes

Takae Kiyama, Ching-Kang Chen, Halit Y Altay, Yu-Jiun Chen, Leviette Sigala, Dan Su, Steven Eliason, Brad A Amendt and Chai-An Mao

Communications biology, Vol.9(1), 347

2026

DOI: 10.1038/s42003-026-09645-4

PMCID: PMC12963404

PMID: 41620469

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Abstract

The intrinsically photosensitive retinal ganglion cells (ipRGC) are the conduit between the retina and brain regions responsible for non-image-forming and image-forming vision. In mice, six ipRGC subtypes have been discovered based on morphological characteristics, functions, and molecular profiles. All ipRGCs arise from Tbr2-expressing RGCs during developmental stages and subsequently diverge and differentiate into the six mature, distinct subtypes in adult retinas. However, the cellular and molecular mechanisms controlling the formation and maturation of the six ipRGC subtypes remain elusive. Here, we demonstrate that two Tbr2-dependent transcription factors, Iroquois‑related homeobox 1 (Irx1) and T-box containing factor 20 (Tbx20), are key downstream transcription factors guiding lineage segregations of Tbr2-expressing RGC into distinct adult ipRGC subtypes. Both factors also control Opn4 expression. Irx1 is expressed in the M3, M4, and M5 subtypes, while Tbx20 is predominantly expressed in M1, M2, M6, and subgroups of M3 and M5. When Irx1 is ablated during retinal development, Opn4 expression is significantly reduced in the M3, M4, and M5 ipRGC groups; however, the formation of Irx1-expressing ipRGCs is not affected. In contrast, when Tbx20 is deleted, a significant number of Tbx20-expressing cells fail to develop while Opn4 expression is down-regulated. These findings reveal two parallel transcription cascades downstream of Tbr2 for controlling ipRGC subtype formation, fate divergence, and maintenance in the adult retina.

Details

Title: Subtitle: Tbr2-dependent parallel pathways regulate the development of distinct ipRGC subtypes
Creators: Takae Kiyama - The University of Texas Health Science Center at Houston
Ching-Kang Chen - The University of Texas at San Antonio Health Science Center
Halit Y Altay - The University of Texas Health Science Center at Houston
Yu-Jiun Chen - The University of Texas at San Antonio Health Science Center
Leviette Sigala - The University of Texas at San Antonio Health Science Center
Dan Su - University of Iowa
Steven Eliason - University of Iowa
Brad A Amendt - University of Iowa
Chai-An Mao - The University of Texas MD Anderson Cancer Center
Resource Type: Journal article
Publication Details: Communications biology, Vol.9(1), 347
DOI: 10.1038/s42003-026-09645-4
PMID: 41620469
PMCID: PMC12963404
NLM abbreviation: Commun Biol
ISSN: 2399-3642
eISSN: 2399-3642
Publisher: Springer Nature; BERLIN
Grant note: EY024376 / U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
Language: English
Electronic publication date: 02/01/2026
Date published: 2026
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Orthodontics; Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9985139318902771

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