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Pax6 regulation of Math5 during mouse retinal neurogenesis.

ABSTRACT: Activation of the bHLH factor Math5 (Atoh7) is an initiating event for mammalian retinal neurogenesis, as it is critically required for retinal ganglion cell formation. However, the cis-regulatory elements and trans-acting factors that control Math5 expression are largely unknown. Using a combination of transgenic mice and bioinformatics, we identified a phylogenetically conserved regulatory element that is required to activate Math5 transcription during early retinal neurogenesis. This element drives retinal expression in vivo, in a cross-species transgenic assay. Previously, Pax6 was shown to be necessary for the initiation of Math5 mRNA expression. We extend this finding by showing that the Math5 retinal enhancer also requires Pax6 for its activation, via Pax6 binding to a highly conserved binding site. In addition, our data reveal that other retinal factors are required for accurate regulation of Math5 by Pax6.

SUBMITTER: Riesenberg AN

PROVIDER: S-EPMC2976517 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Pax6 regulation of Math5 during mouse retinal neurogenesis.

Riesenberg Amy N AN Le Tien T TT Willardsen Minde I MI Blackburn David C DC Vetter Monica L ML Brown Nadean L NL

Genesis (New York, N.Y. : 2000) 20090301 3

Activation of the bHLH factor Math5 (Atoh7) is an initiating event for mammalian retinal neurogenesis, as it is critically required for retinal ganglion cell formation. However, the cis-regulatory elements and trans-acting factors that control Math5 expression are largely unknown. Using a combination of transgenic mice and bioinformatics, we identified a phylogenetically conserved regulatory element that is required to activate Math5 transcription during early retinal neurogenesis. This element ...[more]

PMID: 19208436

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Project description:PurposeA previous study demonstrated that CTCF (CCCTC binding factor) regulates homeobox Pax6 gene expression in early embryonic stages and plays a dominant role in eye development. The purpose of the present study was to explore further the mechanism of CTCF controlling Pax6 gene expression in human retinoblastoma (Rb) cells and in the development of chicken and mouse retinas.MethodsNorthern and Western analyses were used to detect expressions of CTCF and Pax6 in Rb cells. Pax6 transcription reporter and deletion mutants were used to study the regulatory interaction between CTCF and Pax6 in Rb cells and in the retina of chicken embryos. CTCF transgenic chicken embryos and mice were established by lipofection and microinjection of linearized cytomegalovirus (CMV)-CTCF construct into fertilized eggs and mouse oocytes, respectively. Injected oocytes were implanted in the uterus of foster mothers through microinjection into the ovarian duct. The expression of CTCF and Pax6 was determined in embryo sections by immunochemistry.ResultsStimulation of Rb cells with 10% FBS resulted in an increase in CTCF expression and a decrease in Pax6 expression. To study the regulatory mechanism, the Pax6 reporter and its deletion mutant activities were determined in transfected Rb cells and chicken embryonic retinas, revealing that CTCF interacts with the Pax6 gene in Rb cells through transcription control in the 5'-flanking region upstream from the Pax6 P0 promoter. Overexpression of CTCF in Rb cells suppressed Pax6 reporter activity and downregulated endogenous Pax6 expression. In contrast, downregulation of CTCF expression by knockdown of CTCF mRNA using specific small interfering (si)RNA markedly enhanced Pax6 expression in Rb cells. Further study in CTCF transgenic mouse embryos verified that overexpression of CTCF suppressed Pax6 gene expression in the retina.ConclusionsCTCF plays an important role in regulating Pax6 expression in Rb cells and in the developmental retina, and the regulation of Pax6 gene expression by CTCF in the retina is through transcriptional regulation.

Dataset Information

Pax6 regulation of Math5 during mouse retinal neurogenesis.

Publications

Pax6 regulation of Math5 during mouse retinal neurogenesis.

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