title: A chemical genetic screen in zebrafish for pathways interacting with cdx4 in primitive hematopoiesis.
abstract: cdx4, a caudal-related homeodomain-containing transcription factor, functions as a regulator of hox genes, thereby playing a critical role in anterior-posterior (A-P) patterning during embryogenesis. In zebrafish, homozygous deletion of the cdx4 gene results in a mutant phenotype known as kugelig, with aberrant A-P patterning and severe anemia characterized by decreased gata1 expression in the posterior lateral mesoderm. To identify pathways that interact with cdx4 during primitive hematopoiesis, we conducted a chemical genetic screen in the cdx4 mutant background for compounds that increase gata1 expression in cdx4 mutants. Among 2640 compounds that were tested, we discovered two compounds that rescued gata1 expression in the cdx4-mutant embryos. The strongest rescue was observed with bergapten, a psoralen compound found in bergamont oil. Another member of the psoralen family, 8-methoxypsoralen, was also found to rescue gata1 expression in cdx4-mutant embryos. The psoralen compounds also disrupted normal A-P patterning of embryos. These compounds modify the cdx4-mutant phenotype and will help elucidate signaling pathways that act downstream or parallel to the cdx4-hox pathway.
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Paik
authors.forename: Jill L O
authors.initials: JL
authors.lastname: de Jong
authors.forename: Emily
authors.initials: E
authors.lastname: Pugach
authors.forename: Praise
authors.initials: P
authors.lastname: Opara
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005820:Genetic Testing; D006410:Hematopoiesis / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C499644:cdx4 protein, zebrafish