T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/07897 |
| _version_ | 1811253413600559104 |
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| author | Uchenna Emechebe Pavan Kumar P Julian M Rozenberg Bryn Moore Ashley Firment Tooraj Mirshahi Anne M Moon |
| author_facet | Uchenna Emechebe Pavan Kumar P Julian M Rozenberg Bryn Moore Ashley Firment Tooraj Mirshahi Anne M Moon |
| author_sort | Uchenna Emechebe |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:49:40Z |
| format | Article |
| id | doaj.art-2a15d86cd99e45838187888034c4d299 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:49:40Z |
| publishDate | 2016-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-2a15d86cd99e45838187888034c4d2992022-12-22T03:24:25ZengeLife Sciences Publications LtdeLife2050-084X2016-04-01510.7554/eLife.07897T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit numberUchenna Emechebe0Pavan Kumar P1Julian M Rozenberg2Bryn Moore3Ashley Firment4Tooraj Mirshahi5Anne M Moon6https://orcid.org/0000-0002-9090-1093Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, United StatesWeis Center for Research, Geisinger Clinic, Danville, United StatesWeis Center for Research, Geisinger Clinic, Danville, United StatesWeis Center for Research, Geisinger Clinic, Danville, United StatesWeis Center for Research, Geisinger Clinic, Danville, United StatesWeis Center for Research, Geisinger Clinic, Danville, United StatesDepartment of Neurobiology and Anatomy, University of Utah, Salt Lake City, United States; Weis Center for Research, Geisinger Clinic, Danville, United States; Department of Human Genetics, University of Utah, Salt Lake City, United States; Department of Pediatrics, University of Utah, Salt Lake City, United StatesCrucial 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.https://elifesciences.org/articles/07897cilialimb developmenthedgehoggli3kif7tbx3 |
| spellingShingle | Uchenna Emechebe Pavan Kumar P Julian M Rozenberg Bryn Moore Ashley Firment Tooraj Mirshahi Anne M Moon T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number eLife cilia limb development hedgehog gli3 kif7 tbx3 |
| title | T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number |
| title_full | T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number |
| title_fullStr | T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number |
| title_full_unstemmed | T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number |
| title_short | T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number |
| title_sort | t box3 is a ciliary protein and regulates stability of the gli3 transcription factor to control digit number |
| topic | cilia limb development hedgehog gli3 kif7 tbx3 |
| url | https://elifesciences.org/articles/07897 |
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