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PMID: 17919464 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina.

Brain research ·Vol. 1192 ·2008-02-04 ·Pages 99-113

Clark AM, Yun S, Veien ES, Wu YY, Chow RL, Dorsky RI, Levine EM

Abstract

Chx10/Vsx2 and Vsx1 are the only Paired-like CVC (Prd-L:CVC) homeobox genes in the mouse genome. Both are expressed in the retina and have important but distinct roles in retinal development. Mutations in Chx10/Vsx2 cause reduced retinal progenitor cell (RPC) proliferation and an absence of bipolar cells, while mutations in Vsx1 impair differentiation of cone bipolar cells. Given their structural similarities and importance in retinal development, we sought to determine if a regulatory interaction exists between these genes and whether inactivation of both genes blocks initiation of retinal development. We found that Chx10/Vsx2 binds to a specific sequence in the Vsx1 5'-intergenic region and represses the activity of a luciferase reporter under the control of the Vsx1 promoter. This is consistent with our observation that there is an inverse relationship between the levels of Chx10/Vsx2 and Vsx1 immunostaining within the bipolar cell class. Furthermore, Vsx1 mRNA is upregulated in the RPCs of Chx10/Vsx2 deficient mice and zebrafish embryos injected with a chx10/vsx2 morpholino. In mice deficient for both Chx10/Vsx2 and Vsx1 and zebrafish embryos co-injected with chx10/Vsx2 and vsx1 morpholinos, the changes in embryonic retinal development and marker expression are similar in magnitude to embryos with Chx10/Vsx2 loss of function only. From these studies, we propose that Vsx1 is a direct target of Chx10/Vsx2-mediated transcriptional repression. Although Vsx1 mRNA is upregulated in Chx10/Vsx2 deficient RPCs, Vsx1 does not genetically compensate for loss of Chx10/Vsx2, demonstrating that Prd-L:CVC genes, although important, are not absolutely required to initiate retinal development.

MeSH Terms
Animals Cell Differentiation/genetics Cell Line Conserved Sequence/genetics Down-Regulation/genetics Evolution, Molecular Eye Proteins/genetics Gene Expression Regulation, Developmental/genetics Genes, Homeobox/genetics Homeodomain Proteins/genetics Humans Mice Mice, Knockout Promoter Regions, Genetic/genetics RNA, Messenger/metabolism Regulatory Elements, Transcriptional/genetics Repressor Proteins/genetics Retina/cytology,embryology,metabolism Stem Cells/cytology,metabolism Transcription Factors/genetics Up-Regulation/genetics Vertebrates/embryology Zebrafish
Chemicals
Eye Proteins Homeodomain Proteins RNA, Messenger Repressor Proteins Transcription Factors Vsx1 protein, mouse Vsx2 protein, mouse
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Clark Anna M
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT, USA.
Yun Sanghee
Veien Eric S
Wu Yuan Y
Chow Robert L
Dorsky Richard I
Levine Edward M
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Article Info
Journal
Brain research
Abbr.
Brain Res
ISSN
0006-8993
DOI
10.1016/j.brainres.2007.06.007
Published
2008-02-04
Epub
2007-00-18
Pages
99-113
Language
English
Region
Netherlands
NLM ID
0045503
PMCID
PMC3315787
Subset
IM
Grants
NEI NIH HHS · R01-EY0013760 · United States
NEI NIH HHS · R01 EY013760 · United States
NEI NIH HHS · R01 EY013760-01A2 · United States
NEI NIH HHS · R01 EY013760-04 · United States
NEI NIH HHS · R01 EY013760-02 · United States
NEI NIH HHS · R01 EY013760-03 · United States
NEI NIH HHS · EY0014800 · United States
NINDS NIH HHS · R01-NS0053897 · United States
NEI NIH HHS · P30 EY014800 · United States
NINDS NIH HHS · R01 NS053897 · United States
External Links
PubMed source DOI: 10.1016/j.brainres.2007.06.007 PMC Full Text View journal details
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