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Cited by 36Hedgehog Signaling Pathway StudiesCongenital limb and hand anomaliesGenetic and Kidney Cyst Diseases

T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number

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Emechebe, Uchenna, Kumar P, Pavan, Rozenberg, Julian M, Moore, Bryn, Firment, Ashley, Mirshahi, Tooraj, Moon, Anne M·2016·eLife
DOI 10.7554/elife.07897PMC PMC4829432
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Abstract

Crucial roles for T-box3 in development are evident by severe limb malformations and other birth defects caused by T-box3 mutations in humans. Mechanisms whereby T-box3 regulates limb development are poorly understood. We discovered requirements for T-box at multiple stages of mouse limb development and distinct molecular functions in different tissue compartments. Early loss of T-box3 disrupts limb initiation, causing limb defects that phenocopy Sonic Hedgehog (Shh) mutants. Later ablation of T-box3 in posterior limb mesenchyme causes digit loss. In contrast, loss of anterior T-box3 results in preaxial polydactyly, as seen with dysfunction of primary cilia or Gli3-repressor. Remarkably, T-box3 is present in primary cilia where it colocalizes with Gli3. T-box3 interacts with Kif7 and is required for normal stoichiometry and function of a Kif7/Sufu complex that regulates Gli3 stability and processing. Thus, T-box3 controls digit number upstream of Shh-dependent (posterior mesenchyme) and Shh-independent, cilium-based (anterior mesenchyme) Hedgehog pathway function.

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  • TBX3 and TBX2 are closely entangled in other regulatory programs, such as Wnt and Hedgehog signaling, and both are essential for proper limb, lung, and ureter development.

    “TBX3 and TBX2 are closely entangled in other regulatory programs, such as Wnt and Hedgehog signaling, and both are essential for proper limb [8], lung [9], and ureter development [10].”

    From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [8]

    The Results section ('Tbx3 is required for normal limb bud initiation') reports defective limb initiation in Tbx3 mutants, supporting the TBX3 portion of the limb-development claim. The Results section on the Hand2/Shh pathway lists Tbx2 among transcripts reduced after Tbx3 loss, but does not establish that TBX2 itself is essential for limb development. The separate lung and ureter citations are not judged here. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Tbx3 interacts with certain parts of the Wnt and Hedgehog signaling pathways.

    “Interestingly, Tbx3 interacts with certain parts of the Wnt and Hedgehog signaling pathways [8–10].”

    From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [8]

    The Results section reports that Tbx3 interacts with Kif7, a Hedgehog-pathway protein, and that Hedgehog activation changes Tbx3 localization in cilia. The passages found do not establish an interaction with the Wnt signaling pathway (no page numbers are available in our copy), so that part of the claim remains unsupported. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Emechebe, U., Kumar P, P., Rozenberg, J. M., Moore, B., Firment, A., Mirshahi, T., & Moon, A. M.
Affiliations
  • University of Utah (US)
  • Weis Center for Research, Geisinger Clinic, Danville, United States
  • Geisinger Medical Center (US)
Corresponding author
Moon, Anne M
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2016-04-05
Volume
5
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.07897
PMC
PMC4829432
OpenAlex
W2314524563
Cited by
36
References
9
Citations by year
2026: 1 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 5
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
primary cilia, Gli3, Sonic hedgehog signaling, digit number, limb development, preaxial polydactyly, limb mesenchyme, Hedgehog signaling, limb malformations
MeSH terms
Zinc Finger Protein Gli3, Animals, Forelimb, Hindlimb, Nerve Tissue Proteins, Kinesins, Gene Expression Regulation, Developmental, T-Box Domain Proteins, Protein Interaction Mapping, Mice, Kruppel-Like Transcription Factors

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