title: TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.
abstract: TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Pavan
authors.initials: P
authors.lastname: Kumar P
authors.affiliation: Department of Internal Medicine and the Nora Eccles Harrison Cardiovascular Research & Training Institute, University of Utah, Salt Lake City, Utah, United States of America; Department of Anesthesiology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Franklin
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America; Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Uchenna
authors.initials: U
authors.lastname: Emechebe
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Barry
authors.initials: B
authors.lastname: Moore
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Chris
authors.initials: C
authors.lastname: Lehman
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Yandell
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America; Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, United States of America; Department of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America; Molecular Medicine Program, University of Utah, Salt Lake City, Utah, United States of America; Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Moon
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001941:Breast Diseases / Q000235:genetics* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D009154:Mutation; D009421:Nervous System Malformations; D060066:Protein Interaction Maps / Q000235:genetics*; D040901:Proteomics / Q000379:methods; D012322:RNA Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics*; D014457:Ulna / Q000002:abnormalities* / Q000473:pathology
chemical_list: D012322:RNA Precursors; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; C106884:TBX3 protein, human