Tbx5 is required for forelimb bud formation and continued outgrowth

TY - JOUR

T1 - Tbx5 is required for forelimb bud formation and continued outgrowth

AU - Rallis, Charalampos

AU - Bruneau, Benoit G

AU - Del Buono, Jo

AU - Seidman, Christine E

AU - Seidman, J G

AU - Nissim, Sahar

AU - Tabin, Clifford J

AU - Logan, Malcolm P O

PY - 2003/6

Y1 - 2003/6

N2 - Tbx5 is a T-box transcription factor expressed exclusively in the developing forelimb but not in the developing hindlimb of vertebrates. Tbx5 is first detected in the prospective forelimb mesenchyme prior to overt limb bud outgrowth and its expression is maintained throughout later limb development stages. Direct evidence for a role of Tbx5 in forelimb development was provided by the discovery that mutations in human TBX5 cause Holt-Oram Syndrome (HOS), a dominant disorder characterised predominantly by upper(fore) limb defects and heart abnormalities. Misexpression studies in the chick have demonstrated a role for this gene in limb-type specification. Using a conditional knockout strategy in the mouse to delete Tbx5 gene function in the developing forelimb, we demonstrate that this gene is also required at early limb bud stages for forelimb bud development. In addition, by misexpressing dominant-negative and dominant-activated forms of Tbx5 in the chick wing we provide evidence that this gene is also required at later stages of limb bud development for continued limb outgrowth. Our results provide a context to understand the defects observed in HOS caused by haploinsufficiency of TBX5 in human. Moreover, our results also demonstrate that limb bud outgrowth and specification of limb identity are linked by a requirement for Tbx5.

AB - Tbx5 is a T-box transcription factor expressed exclusively in the developing forelimb but not in the developing hindlimb of vertebrates. Tbx5 is first detected in the prospective forelimb mesenchyme prior to overt limb bud outgrowth and its expression is maintained throughout later limb development stages. Direct evidence for a role of Tbx5 in forelimb development was provided by the discovery that mutations in human TBX5 cause Holt-Oram Syndrome (HOS), a dominant disorder characterised predominantly by upper(fore) limb defects and heart abnormalities. Misexpression studies in the chick have demonstrated a role for this gene in limb-type specification. Using a conditional knockout strategy in the mouse to delete Tbx5 gene function in the developing forelimb, we demonstrate that this gene is also required at early limb bud stages for forelimb bud development. In addition, by misexpressing dominant-negative and dominant-activated forms of Tbx5 in the chick wing we provide evidence that this gene is also required at later stages of limb bud development for continued limb outgrowth. Our results provide a context to understand the defects observed in HOS caused by haploinsufficiency of TBX5 in human. Moreover, our results also demonstrate that limb bud outgrowth and specification of limb identity are linked by a requirement for Tbx5.

KW - Animals

KW - Chick Embryo

KW - Embryonic Induction/physiology

KW - Gene Expression Regulation, Developmental/physiology

KW - Limb Buds

KW - Mesoderm/metabolism

KW - Mice

KW - T-Box Domain Proteins/metabolism

KW - Transcription, Genetic/physiology

KW - Upper Extremity/embryology

M3 - Article

C2 - 12736217

SN - 0950-1991

VL - 130

SP - 2741

EP - 2751

JO - Development (Cambridge): for advances in developmental biology and stem cells

JF - Development (Cambridge): for advances in developmental biology and stem cells

IS - 12

ER -