Targeted insertion results in a Rhombomere 2‐specific <i>Hoxa2</i> knockdown and ectopic activation of <i>Hoxa1</i> expression

Ren, Shuyue; Angrand, Pierre‐Olivier; Rijli, Filippo M.

doi:10.1002/dvdy.10171

Cited by 34 publications

(20 citation statements)

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“…Recombinant ES cell clones were generated, and two independent chimeric mice were obtained that provided germ line transmission of the Hoxa1 knocked-in allele. Since the PGK-neomycin cassette could interfere with proper Hoxa1 WM-AA gene expression (36,37), the chimeric males were crossed with a ubiquitously Cre-expressing line (19). The resulting Cre-mediated recombination event left a short 82-bp insert within the intron of the Hoxa1 WM-AA allele, useful for animal genotyping (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Remacle

Abbas

Backer

et al. 2004

Molecular and Cellular Biology

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Homeodomain containing transcription factors of the Hox family play critical roles in patterning the anteroposterior embryonic body axis, as well as in controlling several steps of organogenesis. Several Hox proteins have been shown to cooperate with members of the Pbx family for the recognition and activation of identified target enhancers. Hox proteins contact Pbx via a conserved hexapeptide motif. Previous biochemical studies provided evidence that critical amino acid substitutions in the hexapeptide sequence of Hoxa1 abolish its interaction with Pbx. As a result, these substitutions also abolish Hoxa1 activity on known target enhancers in cellular models, suggesting that Hoxa1 activity relies on its capacity to interact with Pbx. Here, we show that mice with mutations in the Hoxa1 hexapeptide display hindbrain, cranial nerve, and skeletal defects highly reminiscent of those reported for the Hoxa1 loss of function. Since similar hexapeptide mutations in the mouse Hoxb8 and the Drosophila AbdA proteins result in activity modulation and gain of function, our data demonstrate that the functional importance of the hexapeptide in vivo differs according to the Hox proteins.

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Section: Resultsmentioning

confidence: 99%

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

Remacle

Abbas

Backer

et al. 2004

Molecular and Cellular Biology

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“…Irrespective of such unresolved issues, our stable mutant protein, which contains the integral HSR, nuclear localization signal (NLS), SAND, and truncated PHD1 domains, closely emulates the common 13-bp deletion in human APECED patients for which several studies strongly suggest the expression of a stable truncated protein (27)(28)(29). Second, the targeting vector used in the deletion of exon 6 and premature termination of the Aire protein at the end of the SAND domain in Peltonen's mice has a selection cassette that was not removable, raising the possibility of affecting the expression of neighboring genes (51)(52)(53)(54)(55)(56)(57). Third, our model allows previously unappreciated insights into the role of Aire in the maintenance of normal fertility.…”

Section: Discussionmentioning

confidence: 99%

Aire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype

Hubert¹,

Kinkel

Crewther

et al. 2009

The Journal of Immunology

119

146

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Autoimmune regulator (AIRE) is an important transcription regulator that mediates a role in central tolerance via promoting the “promiscuous” expression of tissue-specific Ags in the thymus. Although several mouse models of Aire deficiency have been described, none has analyzed the phenotype induced by a mutation that emulates the common 13-bp deletion in human APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) by disrupting the first plant homeodomain in exon 8. Aire-deficient mice with a corresponding mutation showed some disturbance of the medullary epithelial compartment, but at the phenotypic level their T cell compartment appeared relatively normal in the thymus and periphery. An increase in the number of activated T cells was evident, and autoantibodies against several organs were detected. At the histological level, lymphocytic infiltration of several organs indicated the development of autoimmunity, although symptoms were mild and the quality of life for Aire-deficient mice appeared equivalent to wild-type littermates, with the exception of male infertility. Vβ and CDR3 length analysis suggested that each Aire-deficient mouse developed its own polyclonal autoimmune repertoire. Finally, given the prevalence of candidiasis in APECED patients, we examined the control of infection with Candida albicans in Aire-deficient mice. No increase in disease susceptibility was found for either oral or systemic infection. These observations support the view that additional genetic and/or environmental factors contribute substantially to the overt nature of autoimmunity associated with Aire mutations, even for mutations identical to those found in humans with APECED.

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“…First, some Parkin-deficient mice were generated by using the Pgk-neo r cassette, which can affect the regulation of neighboring genes (34,35) and could produce phenotypes that are not the result of the parkin deletion. Second, testing Parkin-deficient mice on a mixed B6;129 genetic background, as has been done in the current and previous studies, can lead to false-positive findings, depending on the segregation of 129-vs. B6-derived genes.…”

Section: Discussionmentioning

confidence: 99%

Parkin-deficient mice are not a robust model of parkinsonism

Perez

Palmiter

2005

Proc. Natl. Acad. Sci. U.S.A.

418

339

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Mutations in the human parkin gene cause autosomal recessive juvenile parkinsonism, a heritable form of Parkinson's disease (PD). To determine whether mutations in the mouse parkin gene (Park2) also result in a parkinsonian phenotype, we generated mice with a targeted deletion of parkin exon 2. Using an extensive behavioral screen, we evaluated neurological function, motor ability, emotionality, learning, and memory in aged Parkin-deficient mice. The behavioral profile of Parkin-deficient mice on a B6;129S4 genetic background was strikingly similar to that of control mice, and most differences were not reproducible by using coisogenic mice on a 129S4 genetic background. Moreover, catecholamine levels in the striatum, olfactory bulb, and spinal cord of Parkin-deficient mice were normal. In contrast to previous studies using independently generated Parkin-deficient mice, we found no evidence for nigrostriatal, cognitive, or noradrenergic dysfunction. Understanding why Parkin-deficient mice do not exhibit robust signs of parkinsonism could advance knowledge and treatment of PD.mouse behavior ͉ dopamine ͉ norepinephrine ͉ gene knockout ͉ Parkinson P arkinson's disease (PD) is a devastating neurodegenerative disorder that affects Ͼ500,000 people in the United States alone (1). The age-related and progressive signs of PD classically include resting tremor, muscular rigidity, abnormal gait, and slow movement; however, other signs and symptoms associated with parkinsonism can include somatosensory deficits, impaired cognitive function, and psychiatric disturbances (2-4). Many PD signs result from the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopamine replacement medications often succeed in managing parkinsonism; however, these treatments lose effectiveness, have undesirable effects, and do not prevent the underlying neurodegeneration. Understanding the molecular mechanism of dopaminergic neuron degeneration would facilitate the development of therapies that prevent PD.The identification of mutations in single genes that result in familial parkinsonism will help advance our understanding of the molecular mechanism of PD. Mutations in the human parkin gene are responsible for autosomal recessive juvenile parkinsonism (AR-JP), a heritable disease that resembles PD (5). The Parkin protein is a widely expressed, E3 ubiquitin-protein ligase that is thought to target specific proteins for proteasomal degradation (5-7). Presumably, in the absence of Parkin function, these protein targets accumulate to toxic levels and cause dopamine neuron degeneration.To investigate how mutations in parkin lead to parkinsonism, we generated mice with a targeted disruption of Park2. We hypothesized that Parkin-deficient mice would recapitulate the behavioral signs and pathology of AR-JP. During our investigation, several other groups independently generated and described mice with various targeted deletions of the parkin gene (8-11); however, results from these studies have raised many new issues. First, the b...

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Targeted insertion results in a Rhombomere 2‐specific Hoxa2 knockdown and ectopic activation of Hoxa1 expression

Cited by 34 publications

References 65 publications

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

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

Aire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype

Parkin-deficient mice are not a robust model of parkinsonism

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