title: T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number.
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.
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, United States.
authors.forename: Uchenna
authors.initials: U
authors.lastname: Emechebe
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, United States.
authors.forename: Pavan
authors.initials: P
authors.lastname: Kumar P
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, United States.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Rozenberg
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, United States.
authors.forename: Bryn
authors.initials: B
authors.lastname: Moore
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, United States.
authors.forename: Ashley
authors.initials: A
authors.lastname: Firment
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, United States.
authors.forename: Tooraj
authors.initials: T
authors.lastname: Mirshahi
authors.affiliation: Department 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 States.
authors.forename: Anne M
authors.identifier: http://orcid.org/0000-0002-9090-1093
authors.initials: AM
authors.lastname: Moon
mesh_terms: D000818:Animals; D005552:Forelimb / Q000002:abnormalities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D006614:Hindlimb / Q000002:abnormalities / Q000196:embryology*; D016547:Kinesins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D025941:Protein Interaction Mapping; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D000074290:Zinc Finger Protein Gli3
chemical_list: C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D000074290:Zinc Finger Protein Gli3; C543639:Kif7 protein, mouse; D016547:Kinesins
keywords: cilia; developmental biology; gli3; hedgehog; human biology; kif7; limb development; medicine; mouse; stem cells; tbx3