Loss of Function but No Gain of Function Caused by Amino Acid Substitutions in the Hexapeptide of Hoxa1 In Vivo

Remacle, Sophie; Abbas, Leïla; Backer, Olivier De; Pacico, Nathalie; Gavalas, Anthony; Gofflot, Françoise; Picard, Jacques; Rezsöhazy, René

doi:10.1128/mcb.24.19.8567-8575.2004

Cited by 43 publications

(44 citation statements)

References 41 publications

(62 reference statements)

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“…HOXA1 is a key gene in skull development, and it is a retinoic acid (RA) direct target gene (Ijichi and Ijichi, 2002). Mice with mutations in the HOXA1 hexapeptide motif show skeletal defects (Remacle et al, 2004). Similar results were reported by Martinez-Ceballos et al (2005), who showed that the disruption of the HOXA1 gene results in abnormal ossification of the skull.…”

Section: Discussionsupporting

confidence: 58%

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HOX gene analysis in the osteogenic differentiation of human mesenchymal stem cells

et al. 2008

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Human bone marrow-derived mesenchymal stem cells (hMSCs) have the capacity to differentiate into osteoblasts during osteogenesis. Several studies attempted to identify osteogenesis-related genes in hMSCs. Although HOX genes are known to play a pivotal role in skeletogenesis, their function in the osteogenesis of hMSCs has not yet been investigated in detail. Our aim was to characterize the expression of 37 HOX genes by multiplex RT-PCR to identify the ones most probably involved in osteogenic differentiation. The results showed that the expression patterns of four HOX genes were altered during this process. In particular, the expression levels of HOXC13 and HOXD13 were dramatically changed. Real-time PCR and Western blot analysis were performed in order to further analyze the expression of HOXC13 and HOXD13. The qRT-PCR results showed that transcription of HOXC13 was up-regulated by up to forty times, whereas that of HOXD13 was down-regulated by approximately five times after osteogenic differentiation. The Western blot results for the HOXC13 and HOXD13 proteins also corresponded well with the real-time PCR result. These findings suggest that HOXC13 and HOXD13 might be involved in the osteogenic differentiation of hMSCs.

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Section: Discussionsupporting

confidence: 58%

“…It is well known that HOX proteins participate in many common developmental processes during normal embryogenesis. Several reports have indicated that HOX genes play a regulatory role in skeletogenesis (Goff and Tabin, 1997;Kanzler et al, 1998;van den Akker et al, 2001;Remacle et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

HOX gene analysis in the osteogenic differentiation of human mesenchymal stem cells

et al. 2008

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“…Tests of mutant Hox proteins in Drosophila and in mice have demonstrated the importance of the YPWM motif for Hox function in vivo, although both loss-and gain-of-function phenotypes were observed (Chan et al, 1996;; Medina-Martinez and Ramirez-Solis, 2003; Merabet et al, 2003;Remacle et al, 2004;Zhao et al, 1996). In vitro, the YPWM region has been shown to mediate Hox interactions with the PBC family of homeodomain proteins (Chang et al, 1995;Johnson et al, 1995;Knoepfler and Kamps, 1995;Neuteboom et al, 1995;Passner et al, 1999;Phelan et al, 1995;Piper et al, 1999;Shanmugam et al, 1997).…”

Section: Cooperative Repression and The Ubx Ypwm Regionmentioning

confidence: 99%

Evolutionarily conserved domains required for activation and repression functions of the Drosophila Hox protein Ultrabithorax

2005

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While testing the functions of deletion mutants in the Hox protein Ultrabithorax (Ubx), we found that the embryonic repression function of Ubx on Distal-less transcription in limb primordia is highly concentration dependent. The steep sigmoidal relationship between in vivo Ubx concentration and Distal-less repression is dependent on the Ubx YPWM motif. This suggests that Ubx cooperatively assembles a multi-protein repression complex on Distal-less regulatory DNA with the YPWM motif as a key protein-protein interface in this complex. Our deletion mutants also provide evidence for a transcriptional activation domain in the N-terminal 19 amino acids of Ubx. This proposed activation domain contains a variant of the SSYF motif that is found at the N termini of many Hox proteins, and is conserved in the activation domain of another Hox protein, Sex combs reduced. These results suggest that the N-terminal region containing the SSYF motif has been conserved in many Hox proteins for its role in transcriptional activation.

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“…Homozygous HOXA1 mutations, which have occurred in several human populations, are viable but cause either BosleySalih-Alorainy syndrome or Athabascan brainstem dysgenesis syndrome (Bosley et al 2008;Bertrand et al 2011). Surprisingly, homozygous Hoxb1 A1 swapped mice (i.e., mice expressing HoxA1 protein from both Hoxb1 alleles, with no expression of HoxB1) show no detectable phenotypic change relative to wild type under laboratory conditions despite a 15% amino acid sequence difference at the homeodomains and a mere 49% identity overall (Remacle et al 2004;Tvrdik and Capecchi 2006). In hemizygous animals, which express only one Hoxb1 A1 swapped allele over Hoxb1 null, fewer facial motor neurons are generated, resulting in hypomorphism of the seventh cranial nerve.…”

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confidence: 99%

Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice

et al. 2015

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Gene targeting techniques have led to the phenotypic characterization of numerous genes; however, many genes show minimal to no phenotypic consequences when disrupted, despite many having highly conserved sequences. The standard explanation for these findings is functional redundancy. A competing hypothesis is that these genes have important ecological functions in natural environments that are not needed under laboratory settings. Here we discriminate between these hypotheses by competing mice (Mus musculus) whose Hoxb1 gene has been replaced by Hoxa1, its highly conserved paralog, against matched wildtype controls in seminatural enclosures. This Hoxb1 A1 swap was reported as a genetic manipulation resulting in no discernible embryonic or physiological phenotype under standard laboratory tests. We observed a transient decline in first litter size for Hoxb1 A1 homozygous mice in breeding cages, but their fitness was consistently and more dramatically reduced when competing against controls within seminatural populations. Specifically, males homozygous for the Hoxb1 A1 swap acquired 10.6% fewer territories and the frequency of the Hoxb1 A1 allele decreased from 0.500 in population founders to 0.419 in their offspring. The decrease in Hoxb1 A1 frequency corresponded with a deficiency of both Hoxb1 A1 homozygous and heterozygous offspring. These data suggest that Hoxb1 and Hoxa1 are more phenotypically divergent than previously reported and support that sub-and/or neofunctionalization has occurred in these paralogous genes leading to a divergence of gene function and incomplete redundancy. Furthermore, this study highlights the importance of obtaining fitness measures of mutants in ecologically relevant conditions to better understand gene function and evolution.KEYWORDS fitness assay; functional redundancy; Hoxa1; Hoxb1; intraspecific competition; subfunctionalization G ENE targeting techniques have led to the phenotypic characterization of thousands of genes across eukaryotes (for reviews see Thorneycroft et al. 2001;Capecchi 2005;Collins et al. 2007) and this characterization continues as this invaluable technology develops (e.g., Meyer et al. 2012;Hsu et al. 2014). However, an estimated 10-15% of mouse genes show minimal to no phenotypic consequences when disrupted (mouse appears normal), despite many having highly conserved sequences (Barbaric et al. 2007). One explanation for these findings is functional redundancy-genes throughout the genome, typically paralogs of disrupted genes, code for the same, or at least overlapping, functions (Nowak et al. 1997;Kafri et al. 2009). A competing explanation for "no phenotype" gene disruptions is that these genes have important ecological functions in natural environments that are not needed, or are of minimal importance, within laboratory settings. Here we discriminate between these hypotheses by using mice that have experienced a manipulation previously reported to have no embryonic or physiological phenotype, wherein the coding sequence of the Hoxb1 gene has ...

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Loss of Function but No Gain of Function Caused by Amino Acid Substitutions in the Hexapeptide of Hoxa1 In Vivo

Cited by 43 publications

References 41 publications

HOX gene analysis in the osteogenic differentiation of human mesenchymal stem cells

HOX gene analysis in the osteogenic differentiation of human mesenchymal stem cells

Evolutionarily conserved domains required for activation and repression functions of the Drosophila Hox protein Ultrabithorax

Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice

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