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

Ben Abdelkhalek, H and Beckers, A and Schuster-Gossler, K and Pavlova, MN and Burkhardt, H and Lickert, H and Rossant, J and Reinhardt, R and Schalkwyk, LC and Müller, I and Herrmann, BG and Ceolin, M and Rivera-Pomar, R and Gossler, A (2004) 'The mouse homeobox gene Not is required for caudal notochord development and affected by the truncate mutation.' Genes and Development, 18 (14). 1725 - 1736. ISSN 0890-9369

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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 (Nottc) 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 NoteGFP/eGFP, NoteGFP/tc, and Nottc/tc embryos is very similar but slightly more severe in NoteGFP/eGFP than in Nottc/tc embryos. This confirms allelism of truncate and Not, and indicates that tc is not a 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 ntl (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.

Item Type: Article
Subjects: Q Science > QH Natural history > QH426 Genetics
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 03 Feb 2015 15:44
Last Modified: 22 Jun 2021 11:15

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