title: Interactions between Cdx genes and retinoic acid modulate early cardiogenesis.
abstract: Cdx transcription factors regulate embryonic positional identities and have crucial roles in anteroposterior patterning (AP) processes of all three germ layers. Previously we have shown that the zebrafish homologues cdx1a and cdx4 redundantly regulate posterior mesodermal derivatives inducing embryonic blood cell fate specification and patterning of the embryonic kidney. Here we hypothesize that cdx factors restrict formation of anterior mesodermal derivatives such as cardiac cells by imposing posterior identity to developing mesodermal cells. We show that ectopic expression of Cdx1 or Cdx4 applied during the brief window of mesoderm patterning in differentiating murine embryonic stem cell (ESC) strongly suppresses cardiac development as assayed by expression of cardiac genes and formation of embryoid bodies (EB) containing "beating" cell clusters. Conversely, in loss-of-function studies performed in cdx-deficient zebrafish embryos, we observed a dose-dependent expansion of tbx5a(+) anterior-lateral plate mesoderm giving rise to cardiac progenitors. However, further cardiac development of these mesodermal cells required additional suppression of the retinoic acid (RA) pathway, possibly due to differential activity of inhibitory RA signals in cdx mutants. Together, our data suggest that cdx proteins affect cardiogenesis by regulating the formation of cardiogenic mesoderm and together with the RA pathway control the early development of cardiac precursor cells.
authors.affiliation: Department of Hematology and Oncology, University of Tuebingen Medical Center II, Tuebingen, Germany. claudia.lengerke@med.uni-tuebingen.de
authors.forename: Claudia
authors.initials: C
authors.lastname: Lengerke
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wingert
authors.forename: Michael
authors.initials: M
authors.lastname: Beeretz
authors.forename: Matthias
authors.initials: M
authors.lastname: Grauer
authors.forename: Anne G
authors.initials: AG
authors.lastname: Schmidt
authors.forename: Martina
authors.initials: M
authors.lastname: Konantz
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Davidson
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics; D014157:Transcription Factors; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D014212:Tretinoin; D029961:Zebrafish Proteins; C491272:Cdx1 protein, mouse; C084563:Cdx4 protein, mouse; C101538:Mesp1 protein, mouse; C103172:T-box transcription factor 5; C499644:cdx4 protein, zebrafish