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The mouse homeobox gene Not is required for caudal notochord development and affected 1725 by the truncate mutation
Genes Dev. 18, 1725-1736 (2004)
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The floating head (flh) gene in zebrafish encodes a homeodomain protein, which is essential for notochord formation along the entire body axis. flh orthologs, termed Not genes, have been isolated from chick and Xenopus, but no mammalian ortholog has yet been identified. Truncate (tc) is an autosomal recessive mutation in mouse that specifically disrupts the development of the caudal notochord. Here, we demonstrate that truncate arose by a mutation in the mouse Not gene. The truncate allele (Not(tc)) contains a point mutation in the homeobox of Not that changes a conserved Phenylalanine residue in helix 1 to a Cysteine (F20C), and significantly destabilizes the homeodomain. Reversion of F20C in one allele of homozygous tc embryonic stem (ES) cells is sufficient to restore normal notochord formation in completely ES cell-derived embryos. We have generated a targeted mutation of Not by replacing-most of the Not coding sequence, including the homeobox with the eGFP gene. The phenotype of Not(eGFP/eGFP), Not(eGFP/tc), and Not(tc/tc) embryos is very similar but slightly more severe in Not(eGFP/eGFP) than in Not(tc/tc) embryos. This confirms allelism of truncate and Not, and indicates that tc is nota complete null allele. Not expression is abolished in Foxa2 and T mutant embryos, suggesting that Not acts downstream of both genes during notochord development. This is in contrast to zebrafish embryos, in which flh interacts with nt1 (zebrafish T) in a regulatory loop and is essential for development of the entire notochord, and suggests that different genetic control circuits act in different vertebrate species during notochord formation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter notochord development; Not gene; homeodomain protein; FLOOR PLATE; ENGRAILED HOMEODOMAIN; PRIMITIVE STREAK; AXIAL MESODERM; CHICK-EMBRYO; EXPRESSION; ZEBRAFISH; XENOPUS; FATE; ORGANIZER
ISSN (print) / ISBN 0890-9369
Zeitschrift Genes and Development
Quellenangaben Band: 18, Heft: 14, Seiten: 1725-1736
Verlag Cold Spring Harbor Laboratory Press
Begutachtungsstatus Peer reviewed