Abstract
The transcription factor Tbx5 is expressed in the developing heart, eyes and anterior appendages. Mutations in human TBX5 cause Holt–Oram syndrome, a condition characterized by heart and upper limb malformations. Tbx5-knockout mouse embryos have severely impaired forelimb and heart morphogenesis from the earliest stages of their development. However, zebrafish embryos with compromised tbx5 function show a complete absence of pectoral fins, while heart development is disturbed at significantly later developmental stages and eye development remains to be thoroughly analysed. We identified a novel tbx5 gene in zebrafish—tbx5b—that is co-expressed with its paralogue, tbx5a, in the developing eye and heart and hypothesized that functional redundancy could be occurring in these organs in embryos with impaired tbx5a function. We have now investigated the consequences of tbx5a and/or tbx5b downregulation in zebrafish to reveal that tbx5 genes have essential roles in the establishment of cardiac laterality, dorsoventral retina axis organization and pectoral fin development. Our data show that distinct relationships between tbx5 paralogues are required in a tissue-specific manner to ensure the proper morphogenesis of the three organs in which they are expressed. Furthermore, we uncover a novel role for tbx5 genes in the establishment of correct heart asymmetry in zebrafish embryos.
Highlights
Tbx5 codes for a T-domain containing transcription factor that has been characterized in many vertebrate species, where it is widely expressed during the development of the heart, the eyes and the anterior set of appendages [1,2,3]
Mutations in human TBX5 cause Holt – Oram syndrome (HOS; OMIM#142900), an autosomal-dominant ‘heart –hand’ condition characterized by heart and upper limb malformations [4,5]
We identified a novel tbx5 gene in zebrafish—tbx5b—that is co-expressed with its paralogue, referred to as tbx5a, in the developing eye and heart fields and that arose during the teleost-specific genome duplication event that took place during evolution
Summary
Tbx codes for a T-domain containing transcription factor that has been characterized in many vertebrate species, where it is widely expressed during the development of the heart, the eyes and the anterior set of appendages (tetrapod forelimbs and fish pectoral fins) [1,2,3]. Owing to its clinical relevance, several Tbx loss-of-function animal models have been developed to assess the role that this gene may play during the development of the vertebrate heart, limbs and eyes. These studies have shown that in mouse Tbx5-knockout embryos, both forelimb and heart development is severely impaired from the earliest stages of development [6,7,8]. Misexpression of Tbx in the ventral retina produces altered projections of retinal ganglion cell (RGC) axons in chick embryos [9], consistent with a fundamental role for Tbx during eye morphogenesis.
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