Ventricular expression of tbx5 inhibits normal heart chamber development

The T-box gene tbx5 is expressed in the developing heart, forelimb, eye, an d liver in vertebrate embryos during critical stages of morphogenesis and p atterning. In humans, mutations in the TBX5 gene have been associated with Holt-Gram syndrome, which is characterized by developmental anomalies in th e heart and forelimbs. In chicken and mouse embryos, tbx5 expression is ini tiated at the earliest stages of heart formation throughout the heart primo rdia and is colocalized with other cardiac transcription factors such as nk x-2.5 and GATA4. As the heart differentiates, tbx5 expression is restricted to the posterior sinoatrial segments of the heart, consistent with the tim ing of atrial chamber determination. The correlation between tbx5 expressio n and atrial lineage determination was examined in retinoic acid (RA)-treat ed chicken embryos. tbx5 expression is maintained throughout the hearts of RA-treated embryos under conditions that also expand atrial-specific gene e xpression. The downstream effects of persistent tbx5 expression in the vent ricles were examined directly in transgenic mice. Embryos that express tbx5 driven by a beta-myosin heavy chain promoter throughout the primitive hear t tube were generated. Loss of ventricular-specific gene expression and ret ardation of ventricular chamber morphogenesis were observed in these embryo s. These studies provide direct evidence for an essential role for tbx5 in early heart morphogenesis and chamber-specific gene expression. (C) 2000 Ac ademic Press.