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Developmental Biology
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Developmental Biology
Article . 2012
License: Elsevier Non-Commercial
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Developmental Biology
Article . 2012 . Peer-reviewed
License: Elsevier Non-Commercial
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Limb anterior–posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3

Authors: Rowena K. Turnbull; Susan Mackem; Megan Bowers; Alexandra L. Joyner; Elyn Riedel; Zhimin Lao; Liane Eng; +1 Authors

Limb anterior–posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3

Abstract

Anterior-posterior (AP) limb patterning is directed by sonic hedgehog (SHH) signaling from the posteriorly located zone of polarizing activity (ZPA). GLI3 and GLI2 are the transcriptional mediators generally utilized in SHH signaling, and each can function as an activator (A) and repressor (R). Although GLI3R has been suggested to be the primary effector of SHH signaling during limb AP patterning, a role for GLI3A or GLI2 has not been fully ruled out, nor has it been determined whether Gli3 plays distinct roles in limb development at different stages. By conditionally removing Gli3 in the limb at multiple different time points, we uncovered four Gli3-mediated functions in limb development that occur at distinct but partially over-lapping time windows: AP patterning of the proximal limb, AP patterning of the distal limb, regulation of digit number and bone differentiation. Furthermore, by removing Gli2 in Gli3 temporal conditional knock-outs, we uncovered an essential role for Gli2 in providing the remaining posterior limb patterning seen in Gli3 single mutants. To test whether GLIAs or GLIRs regulate different aspects of AP limb patterning and/or digit number, we utilized a knock-in allele in which GLI1, which functions solely as an activator, is expressed in place of the bifunctional GLI2 protein. Interestingly, we found that GLIAs contribute to AP patterning specifically in the posterior limb, whereas GLIRs predominantly regulate anterior patterning and digit number. Since GLI3 is a more effective repressor, our results explain why GLI3 is required only for anterior limb patterning and why GLI2 can compensate for GLI3A in posterior limb patterning. Taken together, our data suggest that establishment of a complete range of AP positional identities in the limb requires integration of the spatial distribution, timing, and dosage of GLI2 and GLI3 activators and repressors.

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Keywords

Gli1, Blotting, Western, Kruppel-Like Transcription Factors, Mice, Transgenic, Nerve Tissue Proteins, Zinc Finger Protein Gli2, Mice, Zinc Finger Protein Gli3, Animals, Hedgehog Proteins, Molecular Biology, In Situ Hybridization, Body Patterning, DNA Primers, Sonic hedgehog, Gene Expression Regulation, Developmental, Extremities, Cell Biology, beta-Galactosidase, Digit patterning, Polydactyly, Tamoxifen, Developmental Biology, Signal Transduction

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    citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    61
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
61
Top 10%
Top 10%
Top 10%
hybrid