Tbx5 Buffers Inherent Left/Right Asymmetry Ensuring Symmetric Forelimb Formation

TY - JOUR

T1 - Tbx5 Buffers Inherent Left/Right Asymmetry Ensuring Symmetric Forelimb Formation

AU - Sulaiman, Fatima A

AU - Nishimoto, Satoko

AU - Murphy, George R F

AU - Kucharska, Anna

AU - Butterfield, Natalie C

AU - Newbury-Ecob, Ruth

AU - Logan, Malcolm P O

PY - 2016/12/19

Y1 - 2016/12/19

N2 - 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.

AB - 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.

KW - Abnormalities, Multiple/genetics

KW - Animals

KW - DNA-Binding Proteins/genetics

KW - Embryo, Mammalian

KW - Embryonic Development/genetics

KW - Forelimb/growth & development

KW - Gene Expression Regulation, Developmental

KW - Heart Defects, Congenital/genetics

KW - Heart Septal Defects, Atrial/genetics

KW - Humans

KW - Limb Buds/growth & development

KW - Limb Deformities, Congenital/genetics

KW - Lower Extremity Deformities, Congenital/genetics

KW - Mice

KW - Somites/growth & development

KW - T-Box Domain Proteins/genetics

KW - Upper Extremity Deformities, Congenital/genetics

U2 - 10.1371/journal.pgen.1006521

DO - 10.1371/journal.pgen.1006521

M3 - Article

C2 - 27992425

SN - 1553-7390

VL - 12

SP - e1006521

JO - PL o S Genetics

JF - PL o S Genetics

IS - 12

ER -