Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate

Wei Liu, Oleg Lagutin, Eric Swindell, Milan Jamrich, Guillermo Oliver

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Retinal degeneration causes vision impairment and blindness in humans. If one day we are to harness the potential of stem cell-based cell replacement therapies to treat these conditions, it is imperative that we better understand normal retina development. Currently, the genes and mechanisms that regulate the specification of the neuroretina during vertebrate eye development remain unknown. Here, we identify sine oculis-related homeobox 3 (Six3) as a crucial player in this process in mice. In Six3 conditional-mutant mouse embryos, specification of the neuroretina was abrogated, but that of the retinal pigmented epithelium was normal. Conditional deletion of Six3 did not affect the initial development of the optic vesicle but did arrest subsequent neuroretina specification. Ectopic rostral expansion of Wnt8b expression was the major response to Six3 deletion and the leading cause for the specific lack of neuroretina, as ectopic Wnt8b expression in transgenic embryos was sufficient to suppress neuroretina specification. Using chromatin immunoprecipitation assays, we identified Six3-responsive elements in the Wnt8b locus and demonstrated that Six3 directly repressed Wnt8b expression in vivo. Our findings provide a molecular framework to the program leading to neuroretina differentiation and may be relevant for the development of novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation.

Original languageEnglish (US)
Pages (from-to)3568-3577
Number of pages10
JournalJournal of Clinical Investigation
Volume120
Issue number10
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

Fingerprint

Neural Plate
Embryonic Structures
Eye Abnormalities
Retinal Degeneration
Homeobox Genes
Chromatin Immunoprecipitation
Blindness
Cell- and Tissue-Based Therapy
Vertebrates
Retina
Stem Cells
Epithelium
Genes
Ectopic Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate. / Liu, Wei; Lagutin, Oleg; Swindell, Eric; Jamrich, Milan; Oliver, Guillermo.

In: Journal of Clinical Investigation, Vol. 120, No. 10, 01.10.2010, p. 3568-3577.

Research output: Contribution to journalArticle

Liu, Wei ; Lagutin, Oleg ; Swindell, Eric ; Jamrich, Milan ; Oliver, Guillermo. / Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 10. pp. 3568-3577.
@article{d7065da24b2c496180ea123abfa96393,
title = "Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate",
abstract = "Retinal degeneration causes vision impairment and blindness in humans. If one day we are to harness the potential of stem cell-based cell replacement therapies to treat these conditions, it is imperative that we better understand normal retina development. Currently, the genes and mechanisms that regulate the specification of the neuroretina during vertebrate eye development remain unknown. Here, we identify sine oculis-related homeobox 3 (Six3) as a crucial player in this process in mice. In Six3 conditional-mutant mouse embryos, specification of the neuroretina was abrogated, but that of the retinal pigmented epithelium was normal. Conditional deletion of Six3 did not affect the initial development of the optic vesicle but did arrest subsequent neuroretina specification. Ectopic rostral expansion of Wnt8b expression was the major response to Six3 deletion and the leading cause for the specific lack of neuroretina, as ectopic Wnt8b expression in transgenic embryos was sufficient to suppress neuroretina specification. Using chromatin immunoprecipitation assays, we identified Six3-responsive elements in the Wnt8b locus and demonstrated that Six3 directly repressed Wnt8b expression in vivo. Our findings provide a molecular framework to the program leading to neuroretina differentiation and may be relevant for the development of novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation.",
author = "Wei Liu and Oleg Lagutin and Eric Swindell and Milan Jamrich and Guillermo Oliver",
year = "2010",
month = "10",
day = "1",
doi = "10.1172/JCI43219",
language = "English (US)",
volume = "120",
pages = "3568--3577",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

TY - JOUR

T1 - Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate

AU - Liu, Wei

AU - Lagutin, Oleg

AU - Swindell, Eric

AU - Jamrich, Milan

AU - Oliver, Guillermo

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Retinal degeneration causes vision impairment and blindness in humans. If one day we are to harness the potential of stem cell-based cell replacement therapies to treat these conditions, it is imperative that we better understand normal retina development. Currently, the genes and mechanisms that regulate the specification of the neuroretina during vertebrate eye development remain unknown. Here, we identify sine oculis-related homeobox 3 (Six3) as a crucial player in this process in mice. In Six3 conditional-mutant mouse embryos, specification of the neuroretina was abrogated, but that of the retinal pigmented epithelium was normal. Conditional deletion of Six3 did not affect the initial development of the optic vesicle but did arrest subsequent neuroretina specification. Ectopic rostral expansion of Wnt8b expression was the major response to Six3 deletion and the leading cause for the specific lack of neuroretina, as ectopic Wnt8b expression in transgenic embryos was sufficient to suppress neuroretina specification. Using chromatin immunoprecipitation assays, we identified Six3-responsive elements in the Wnt8b locus and demonstrated that Six3 directly repressed Wnt8b expression in vivo. Our findings provide a molecular framework to the program leading to neuroretina differentiation and may be relevant for the development of novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation.

AB - Retinal degeneration causes vision impairment and blindness in humans. If one day we are to harness the potential of stem cell-based cell replacement therapies to treat these conditions, it is imperative that we better understand normal retina development. Currently, the genes and mechanisms that regulate the specification of the neuroretina during vertebrate eye development remain unknown. Here, we identify sine oculis-related homeobox 3 (Six3) as a crucial player in this process in mice. In Six3 conditional-mutant mouse embryos, specification of the neuroretina was abrogated, but that of the retinal pigmented epithelium was normal. Conditional deletion of Six3 did not affect the initial development of the optic vesicle but did arrest subsequent neuroretina specification. Ectopic rostral expansion of Wnt8b expression was the major response to Six3 deletion and the leading cause for the specific lack of neuroretina, as ectopic Wnt8b expression in transgenic embryos was sufficient to suppress neuroretina specification. Using chromatin immunoprecipitation assays, we identified Six3-responsive elements in the Wnt8b locus and demonstrated that Six3 directly repressed Wnt8b expression in vivo. Our findings provide a molecular framework to the program leading to neuroretina differentiation and may be relevant for the development of novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation.

UR - http://www.scopus.com/inward/record.url?scp=77957839806&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957839806&partnerID=8YFLogxK

U2 - 10.1172/JCI43219

DO - 10.1172/JCI43219

M3 - Article

VL - 120

SP - 3568

EP - 3577

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 10

ER -