title: Histone deacetylase inhibitor Trichostatin A induces neural tube defects and promotes neural crest specification in the chicken neural tube.
abstract: Epigenetic mechanisms serve as key regulatory elements during vertebrate embryogenesis. Histone acetylation levels, controlled by the opposing action of histone acetyl transferases (HATs) and histone deacetylases (HDACs), influence the accessibility of DNA to transcription factors and thereby dynamically regulate transcriptional programs. HDACs execute important functions in the control of proliferation, differentiation, and the establishment of cell identities during embryonic development. To investigate the global role of the HDAC family during neural tube development, we employed Trichostatin A (TSA) to locally block enzymatic HDAC activity in chick embryos in ovo. We found that TSA treatment induces neural tube defects at the level of the posterior neuropore, ranging from slight undulations to a complete failure of neural tube closure. This phenotype is accompanied by morphological changes in neuroepithelial cells and induction of apoptosis. As a molecular consequence of HDAC inhibition, we observed a timely deregulated cadherin switching in the dorsal neural tube, illustrated by induction of Cadherin 6B as well as reciprocal downregulation of N-Cadherin expression. Concomitantly, several neural crest specific markers, including Bmp4, Pax3, Sox9 and Sox10 are induced, causing a premature loss of epithelial characteristics. Our findings provide evidence that HDAC function is crucial to control the regulatory circuits operating during trunk neural crest development and neural tube closure.
authors: Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria. christina.murko@meduniwien.ac.at
authors: Christina
authors: C
authors: Murko
authors: Sabine
authors: S
authors: Lagger
authors: Marianne
authors: M
authors: Steiner
authors: Christian
authors: C
authors: Seiser
authors: Christian
authors: C
authors: Schoefer
authors: Oliver
authors: O
authors: Pusch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002642:Chick Embryo; D056572:Histone Deacetylase Inhibitors / Q000633:toxicity*; D006877:Hydroxamic Acids / Q000633:toxicity*; D009432:Neural Crest / Q000187:drug effects* / Q000196:embryology; D054259:Neural Tube / Q000187:drug effects / Q000196:embryology; D009436:Neural Tube Defects / Q000139:chemically induced*; D046569:Neuroepithelial Cells / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014157:Transcription Factors; C012589:trichostatin A