The Atoh7 remote enhancer provides transcriptional robustness during retinal ganglion cell development. Proc Natl Acad Sci U S A 2020 Sep 01;117(35):21690-21700
Date
08/21/2020Pubmed ID
32817515Pubmed Central ID
PMC7474671DOI
10.1073/pnas.2006888117Scopus ID
2-s2.0-85090505889 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
The retinal ganglion cell (RGC) competence factor ATOH7 is dynamically expressed during retinal histogenesis. ATOH7 transcription is controlled by a promoter-adjacent primary enhancer and a remote shadow enhancer (SE). Deletion of the ATOH7 human SE causes nonsyndromic congenital retinal nonattachment (NCRNA) disease, characterized by optic nerve aplasia and total blindness. We used genome editing to model NCRNA in mice. Deletion of the murine SE reduces Atoh7 messenger RNA (mRNA) fivefold but does not recapitulate optic nerve loss; however, SEdel/knockout (KO) trans heterozygotes have thin optic nerves. By analyzing Atoh7 mRNA and protein levels, RGC development and survival, and chromatin landscape effects, we show that the SE ensures robust Atoh7 transcriptional output. Combining SE deletion and KO and wild-type alleles in a genotypic series, we determined the amount of Atoh7 needed to produce a normal complement of adult RGCs, and the secondary consequences of graded reductions in Atoh7 dosage. Together, these data reveal the workings of an evolutionary fail-safe, a duplicate enhancer mechanism that is hard-wired in the machinery of vertebrate retinal ganglion cell genesis.
Author List
Miesfeld JB, Ghiasvand NM, Marsh-Armstrong B, Marsh-Armstrong N, Miller EB, Zhang P, Manna SK, Zawadzki RJ, Brown NL, Glaser TAuthor
Joel Bryan Miesfeld PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBasic Helix-Loop-Helix Transcription Factors
Cell Differentiation
Embryo, Mammalian
Female
Gene Expression Regulation, Developmental
Male
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins
Neurogenesis
Optic Nerve
Regulatory Sequences, Nucleic Acid
Retina
Retinal Ganglion Cells
Transcription Factors
