Abstract
SummaryThe design of effective cell replacement therapies requires detailed knowledge of how embryonic stem cells form primary tissues, such as mesoderm or neurectoderm that later become skeletal muscle or nervous system. Members of the T-box transcription factor family are key in the formation of these primary tissues, but their underlying molecular activities are poorly understood. Here, we define in vivo genome-wide regulatory inputs of the T-box proteins Brachyury, Eomesodermin, and VegT, which together maintain neuromesodermal stem cells and determine their bipotential fates in frog embryos. These T-box proteins are all recruited to the same genomic recognition sites, from where they activate genes involved in stem cell maintenance and mesoderm formation while repressing neurogenic genes. Consequently, their loss causes embryos to form an oversized neural tube with no mesodermal derivatives. This collaboration between T-box family members thus ensures the continuous formation of correctly proportioned neural and mesodermal tissues in vertebrate embryos during axial elongation.
Highlights
As the vertebrate embryo elongates along its anteroposterior axis, primary tissues are produced in a continuous fashion to form trunk and tail
Xbra Is Stably Recruited to Motif Variants in Early Development To discover how T-box transcription factor (TF) regulate primary tissue formation in vivo, a genome-wide binding map was first created for Xbra in X. tropicalis gastrula embryos by chromatin immunoprecipitation coupled to deep sequencing (ChIP-seq) (Figure 1A)
A de novo search for enriched motifs at Xbra binding sites identified four related motif variants (v1–v4), which, with some overlapping coverage, together account for 82% of binding sites detected at the gastrula stage, suggesting that they are involved in Xbra binding (Figure 1C)
Summary
As the vertebrate embryo elongates along its anteroposterior axis, primary tissues are produced in a continuous fashion to form trunk and tail. This process is thought to occur as a continuation of gastrulation, during which period primary tissues, such as neurectoderm and mesoderm, emerge for the first time. Previous analyses of Brachyury (Xbra), Eomes, and VegT in the Xenopus embryo have focused on their expression patterns, their powerful transactivation activities, and their ability to cause isolated ectodermal tissue to activate mesoderm-specific genes (Showell et al, 2004). The way in which T-box TFs exert such profound effects in vertebrate embryos during normal development remains poorly understood
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