Abstract
SummaryT-box transcription factors T/Brachyury homolog A (Ta) and Tbx16 are essential for correct mesoderm development in zebrafish. The downstream transcriptional networks guiding their functional activities are poorly understood. Additionally, important contributions elsewhere are likely masked due to redundancy. Here, we exploit functional genomic strategies to identify Ta and Tbx16 targets in early embryogenesis. Surprisingly, we discovered they not only activate mesodermal gene expression but also redundantly regulate key endodermal determinants, leading to substantial loss of endoderm in double mutants. To further explore the gene regulatory networks (GRNs) governing endoderm formation, we identified targets of Ta/Tbx16-regulated homeodomain transcription factor Mixl1, which is absolutely required in zebrafish for endoderm formation. Interestingly, we find many endodermal determinants coordinately regulated through common genomic occupancy by Mixl1, Eomesa, Smad2, Nanog, Mxtx2, and Pou5f3. Collectively, these findings augment the endoderm GRN and reveal a panel of target genes underlying the Ta, Tbx16, and Mixl1 mutant phenotypes.
Highlights
The primary germ layers of the vertebrate embryo—endoderm, mesoderm, and ectoderm—are specified early in development
We discovered that T/Brachyury homolog A (Ta)/Tbx16 genomic binding substantially overlaps and provide evidence that use of common cis-regulatory modules (CRMs) accounts for their functional redundancy (Garnett et al, 2009)
Through characterizing genome-wide binding profiles of these transcription factors (TFs), we have identified a set of common target CRMs and regulated genes that can account for the action of Ta and Tbx16 in formation of mesoderm and endoderm
Summary
The primary germ layers of the vertebrate embryo—endoderm, mesoderm, and ectoderm—are specified early in development. Ta is required for notochord formation and it acts synergistically with its paralog, Tb, in posterior somite formation (Halpern et al, 1993; Martin and Kimelman, 2008; Schulte-Merker et al, 1994). Another T-box TF, Tbx, plays a key role in zebrafish mesoderm formation though directing migration of mesodermal progenitors during gastrulation (Ho and Kane, 1990). In Xenopus T, Eomes and VegT (ortholog of Tbx16; Griffin et al, 1998) redundantly regulate neuromesodermal bipotency (Gentsch et al, 2013)
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