Document Detail


Reprogramming amacrine and photoreceptor progenitors into retinal ganglion cells by replacing Neurod1 with Atoh7.
MedLine Citation:
PMID:  23293286     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The specification of the seven retinal cell types from a common pool of retina progenitor cells (RPCs) involves complex interactions between the intrinsic program and the environment. The proneural basic helix-loop-helix (bHLH) transcriptional regulators are key components for the intrinsic programming of RPCs and are essential for the formation of the diverse retinal cell types. However, the extent to which an RPC can re-adjust its inherent program and the mechanisms through which the expression of a particular bHLH factor influences RPC fate is unclear. Previously, we have shown that Neurod1 inserted into the Atoh7 locus activates the retinal ganglion cell (RGC) program in Atoh7-expressing RPCs but not in Neurod1-expressing RPCs, suggesting that Atoh7-expressing RPCs are not able to adopt the cell fate determined by Neurod1, but rather are pre-programmed to produce RGCs. Here, we show that Neurod1-expressing RPCs, which are destined to produce amacrine and photoreceptor cells, can be re-programmed into RGCs when Atoh7 is inserted into the Neurod1 locus. These results suggest that Atoh7 acts dominantly to convert a RPC subpopulation not destined for an RGC fate to adopt that fate. Thus, Atoh7-expressing and Neurod1-expressing RPCs are intrinsically different in their behavior. Additionally, ChIP-Seq analysis identified an Atoh7-dependent enhancer within the intronic region of Nrxn3. The enhancer recognized and used Atoh7 in the developing retina to regulate expression of Nrxn3, but could be forced to use Neurod1 when placed in a different regulatory context. The results indicate that Atoh7 and Neurod1 activate distinct sets of genes in vivo, despite their common DNA-binding element.
Authors:
Chai-An Mao; Jang-Hyeon Cho; Jing Wang; Zhiguang Gao; Ping Pan; Wen-Wei Tsai; Laura J Frishman; William H Klein
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  140     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-07     Completed Date:  2013-03-07     Revised Date:  2014-04-28    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  541-51     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amacrine Cells / cytology*,  metabolism
Animals
Basic Helix-Loop-Helix Transcription Factors / genetics,  metabolism*
Cell Differentiation
Chromatin Immunoprecipitation
Electroretinography
Embryo, Mammalian / cytology,  metabolism
Enhancer Elements, Genetic
Gene Expression Regulation, Developmental
Genetic Loci
Immunohistochemistry
Introns
Mice
Nerve Tissue Proteins / genetics,  metabolism*
Nuclear Reprogramming*
Photoreceptor Cells / cytology,  metabolism
Protein Binding
Retina / cytology,  embryology,  metabolism
Retinal Ganglion Cells / cytology*,  metabolism
Stem Cells / cytology,  metabolism
Grant Support
ID/Acronym/Agency:
CA016672/CA/NCI NIH HHS; EY010608-139005/EY/NEI NIH HHS; EY011930/EY/NEI NIH HHS; EY06671/EY/NEI NIH HHS; P30 CA016672/CA/NCI NIH HHS; P30 EY007551/EY/NEI NIH HHS; R01 EY011930/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/Atoh7 protein, mouse; 0/Basic Helix-Loop-Helix Transcription Factors; 0/Nerve Tissue Proteins; 0/Neurod1 protein, mouse
Comments/Corrections

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