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The mouse homeobox gene <i>Not</i> is required for caudal notochord development and affected by the truncate mutation

Ben Abdelkhalek, Hanaa and Beckers, Anja and Schuster-Gossler, Karin and Pavlova, Maria N and Burkhardt, Hannelore and Lickert, Heiko and Rossant, Janet and Reinhardt, Richard and Schalkwyk, Leonard C and Müller, Ines and Herrmann, Bernhard G and Ceolin, Marcelo and Rivera-Pomar, Rolando and Gossler, Achim (2004) 'The mouse homeobox gene <i>Not</i> is required for caudal notochord development and affected by the truncate mutation.' Genes &amp; Development, 18 (14). pp. 1725-1736. ISSN 0890-9369

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Abstract

<jats:p>The floating head (<jats:italic>flh</jats:italic>) gene in zebrafish encodes a homeodomain protein, which is essential for notochord formation along the entire body axis. <jats:italic>flh</jats:italic> orthologs, termed <jats:italic>Not</jats:italic> genes, have been isolated from chick and <jats:italic>Xenopus</jats:italic>, but no mammalian ortholog has yet been identified. Truncate (<jats:italic>tc</jats:italic>) 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 <jats:italic>Not</jats:italic> gene. The truncate allele (<jats:italic>Not<jats:sup>tc</jats:sup></jats:italic>) contains a point mutation in the homeobox of <jats:italic>Not</jats:italic> 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 <jats:italic>tc</jats:italic> embryonic stem (ES) cells is sufficient to restore normal notochord formation in completely ES cell-derived embryos. We have generated a targeted mutation of <jats:italic>Not</jats:italic> by replacing most of the <jats:italic>Not</jats:italic> coding sequence, including the homeobox with the <jats:italic>eGFP</jats:italic> gene. The phenotype of <jats:italic>Not<jats:sup>eGFP/eGFP</jats:sup></jats:italic>, <jats:italic>Not<jats:sup>eGFP/tc</jats:sup></jats:italic>, and <jats:italic>Not<jats:sup>tc/tc</jats:sup></jats:italic> embryos is very similar but slightly more severe in <jats:italic>Not<jats:sup>eGFP/eGFP</jats:sup></jats:italic> than in <jats:italic>Not<jats:sup>tc/tc</jats:sup></jats:italic> embryos. This confirms allelism of truncate and <jats:italic>Not</jats:italic>, and indicates that <jats:italic>tc</jats:italic> is not a complete null allele. <jats:italic>Not</jats:italic> expression is abolished in <jats:italic>Foxa2</jats:italic> and <jats:italic>T</jats:italic> mutant embryos, suggesting that <jats:italic>Not</jats:italic> acts downstream of both genes during notochord development. This is in contrast to zebrafish embryos, in which <jats:italic>flh</jats:italic> interacts with <jats:italic>ntl</jats:italic> (zebrafish <jats:italic>T</jats:italic>) 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.</jats:p>

Item Type: Article
Uncontrolled Keywords: notochord development; Not gene; homeodomain protein
Subjects: Q Science > QH Natural history > QH426 Genetics
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 03 Feb 2015 15:44
Last Modified: 12 Apr 2022 13:39
URI: http://repository.essex.ac.uk/id/eprint/10982

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