title: Tbx5 Buffers Inherent Left/Right Asymmetry Ensuring Symmetric Forelimb Formation.
abstract: The forelimbs and hindlimbs of vertebrates are bilaterally symmetric. The mechanisms that ensure symmetric limb formation are unknown but they can be disrupted in disease. In Holt-Oram Syndrome (HOS), caused by mutations in TBX5, affected individuals have left-biased upper/forelimb defects. We demonstrate a role for the transcription factor Tbx5 in ensuring the symmetric formation of the left and right forelimb. In our mouse model, bilateral hypomorphic levels of Tbx5 produces asymmetric forelimb defects that are consistently more severe in the left limb than the right, phenocopying the left-biased limb defects seen in HOS patients. In Tbx hypomorphic mutants maintained on an INV mutant background, with situs inversus, the laterality of defects is reversed. Our data demonstrate an early, inherent asymmetry in the left and right limb-forming regions and that threshold levels of Tbx5 are required to overcome this asymmetry to ensure symmetric forelimb formation.
authors.affiliation: Division of Developmental Biology, MRC-National Institute for Medical Research, Mill Hill, London, England.
authors.forename: Fatima A
authors.identifier: http://orcid.org/0000-0003-2053-1186
authors.initials: FA
authors.lastname: Sulaiman
authors.affiliation: Division of Developmental Biology, MRC-National Institute for Medical Research, Mill Hill, London, England.|Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, England.
authors.forename: Satoko
authors.initials: S
authors.lastname: Nishimoto
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, England.|Dept of Plastic & Reconstructive Surgery, Great Ormond St Hospital for Children NHS Foundation Trust, London, England.
authors.forename: George R F
authors.identifier: http://orcid.org/0000-0001-9653-2527
authors.initials: GR
authors.lastname: Murphy
authors.affiliation: Division of Developmental Biology, MRC-National Institute for Medical Research, Mill Hill, London, England.
authors.forename: Anna
authors.initials: A
authors.lastname: Kucharska
authors.affiliation: Division of Developmental Biology, MRC-National Institute for Medical Research, Mill Hill, London, England.
authors.forename: Natalie C
authors.identifier: http://orcid.org/0000-0002-5209-7508
authors.initials: NC
authors.lastname: Butterfield
authors.affiliation: Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, St. Michaels's Hospital, Bristol, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Newbury-Ecob
authors.affiliation: Division of Developmental Biology, MRC-National Institute for Medical Research, Mill Hill, London, England.|Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, England.
authors.forename: Malcolm P O
authors.initials: MP
authors.lastname: Logan
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D005552:Forelimb / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology; D006344:Heart Septal Defects, Atrial / Q000235:genetics / Q000473:pathology; D006801:Humans; D018878:Limb Buds / Q000254:growth & development; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D038061:Lower Extremity Deformities, Congenital / Q000235:genetics / Q000473:pathology; D051379:Mice; D019170:Somites / Q000254:growth & development; D020825:T-Box Domain Proteins / Q000235:genetics*; D038062:Upper Extremity Deformities, Congenital / Q000235:genetics / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5