Neomorphic agouti mutations in obese yellow mice

Duhl, David M.; Vrieling, Harry; Miller, Kimberly A.; Wolff, George L.; Barsh, Gregory S.

doi:10.1038/ng0994-59

Cited by 421 publications

(340 citation statements)

References 33 publications

Supporting

Mentioning

323

Contrasting

Unclassified

Order By: Relevance

“…The intermediate yellow allele of Agouti (A iy ) is an antisense-orientation IAP insertion 5′ to the first coding exon. Ectopic expression of Agouti from the LTR promoter of this insertion results in hypo-pigmentation and obesity 15 . Mvb1 does not affect the extent or timing of pigmentation or weight gain in A iy mutant animals.…”

Section: Mvb1 Is Selective For Class Of Retrovirus and Mutagenic Mechmentioning

confidence: 99%

A natural allele of Nxf1 suppresses retrovirus insertional mutations

et al. 2003

View full text Add to dashboard Cite

Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The Modifier-of-vibrator-1 locus controls level of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the pitpn vb tremor mutation and the Eya1 BOR model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between mRNA export receptor and pre-mRNA processing. Population structure of the suppressing allele in wild M. m. castaneus suggests selective advantage. A congenic Mvb1 CAST allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.Mus musculus is a complex species group with subpopulations that have diverged and hybridized since becoming commensal with humans some 10,000 years ago. Allopatric divergence and re-hybridization of mouse lineages are thought to contribute to the diversity and activity of retroviral elements in the current mouse genomes 1,2 . Host genes that can NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript influence the expression of newly introduced (or newly mobilized) viral elements might be selected for variants that blunt these effects. Our results suggest that Mvb1 is such a locus.Mvb1 was originally identified as a strain-derived locus that modifies the neurological mutant, vibrator 3. The vibrator (vb) mutation is a hypomorphic allele of the phosphatidylinositol transfer protein α (PITPα) gene (pitpn) caused by the insertion of an endogenous retrovirus (intracisternal A particle, or IAP) into the fourth intron of the gene, resulting in 5 to 10-fold loss of PITPα expression. Homozygous vibrator mice show severe action tremor, progressive degeneration of interneurons in the brain stem and spinal cord, and uniform juvenile lethality. However, vibrator mice carrying Mvb1 alleles from the wild-derived CAST/Ei inbred strain show reduced tremor severity and survive to adulthood. In principle, this could be due to a change in physiological requirement for PITPα function or to a change in the steady-state expression level of PITPα derived from the mutant allele. RESULTS Mvb1 is a dosage-sensitive modifier of vibrator RNA accumulationMvb1 modifies the severity of vibrator tremor and the associated juvenile lethality 3 . To examine this effect in more detail, we monitored the longevity of vb mutant mice congenic on a C57BL/6J (B6) strain background with zero, one or two CAST/Ei alleles of Mvb1 ( Figure 1a). Consistent with our behavioral observations, the longevity data indicate a semi-dominant mode of action and high penetrance.To extend these observations to the cellular level, we examined histology of vibrator animals homozygous for either the B6 or CAST allele of Mvb1 (Figure 1b To ask whether Mvb1 acts by altering RNA levels from the mutant...

show abstract

Section: Mvb1 Is Selective For Class Of Retrovirus and Mutagenic Mechmentioning

confidence: 99%

A natural allele of Nxf1 suppresses retrovirus insertional mutations

et al. 2003

View full text Add to dashboard Cite

show abstract

“…This may suggest that the transposition into the IL-3 gene locus is a frequent event in some kind of cell types. The presence of such a sensitive locus can be proposed based on recent evidence of insertions of IAP elements into the agouti locus in germline cells in three different hair color mutant mice [18,19]. At present, we cannot exclude possibility that we could accidentally found the integrated leukemia without selection.…”

Section: Discussionmentioning

confidence: 87%

“…Additionally, an unusual long direct repeat of mouse DNA of 82 bp in length was generated at the insertion site of the lAP element, although the target duplication is no more than 6 bp in length in all the reported sequences suggesting a retroviral-like integration mechanism [3,5,6,8,[11][12][13][14][15][16][17][18][19]. The long target duplication may reflect a specific event which occurs during radiation-induced leukemogenesis.…”

Section: Introductionmentioning

confidence: 99%

Unusual long target duplication by insertion of intracisternal A‐particle element in radiation‐induced acute myeloid leukemia cells in mouse

Tanaka¹,

Ishiguro²

1995

FEBS Letters

View full text Add to dashboard Cite

Retrotransmission into the IL-31GM-CSF gene locus by the retrotransposon intracisternal A-particle (IAP) had been observed in distinct tumor cell lines. We analyzed the locus in genomes from 7 different myeloid leukemia cell strains which were originally generated by whole-body X-irradiation of the inbred C3H/He mice at a dose of 3 Gy and maintained by in vivo passage. In one leukemia cell strain out of 7 such cases, RFLP of an allele of the interleukin-3 gene was found. Sequence analysis after cloning from the genomic library showed that a type IA2 IAP element was inserted in the region upstream of the IL-3 gene in the head-to-head orientation. This suggests that the locus in myeloid cells is sensitive for integration of IAP elements. Additionally, an unusual long target duplication of 82 bp, 14-fold larger than normal one, was found at the junction of the element. This suggests the possibility of a radiation-induced integration mechanism which is distinct from normal retrotransmission. Key words:Retrotransposon; Intracisternal A-particle; Myeloid leukemia; Target duplication; Interleukin-3 gene; Genomic DNA cloning with gene rearrangements of IL-3 by retrotransmission should be detected. To confirm this supposition as well as to study the chronic effects of radiation, we used radiation-induced acute myeloid leukemia cells from the C3H/He mouse for analysis. Approximately 20-30% of whole-body X-irradiated C3H/He mice develop acute myeloid leukemia within 2 years with chromosomal aberrations [9,10]. Each leukemia cell strain from different individuals should be an 'independent' leukemia since they became tumorigenic by separate processes. In leukemia cells, not only tumor-specific but also radiation-specific events may be recorded in the genome.We analyzed this locus and found integration of the IAP element in the 1L-3 gene in one leukemia cell strain from a total of 7 independent leukemias. Additionally, an unusual long direct repeat of mouse DNA of 82 bp in length was generated at the insertion site of the lAP element, although the target duplication is no more than 6 bp in length in all the reported sequences suggesting a retroviral-like integration mechanism [3,5,6,8,[11][12][13][14][15][16][17][18][19]. The long target duplication may reflect a specific event which occurs during radiation-induced leukemogenesis.

show abstract

“…The A vy allele is a dominant mutation of the agouti (A) locus, caused by the insertion of an intracisternal A-particle (IAP) retrotransposon upstream of the agouti coding exons. A cryptic promoter in the proximal end of the A vy IAP promotes constitutive ectopic expression of the agouti gene, resulting in a yellow coat colour (Duhl et al, 1994). However, DNA methylation at this promoter results in its silencing and the agouti colour is expressed (Morgan et al, 1999).…”

Section: Transgenerational Epigenetic Inheritance Studies In Mammalsmentioning

confidence: 99%

Epigenetics: a possible role in acute and transgenerational regulation of dairy cow milk production

Singh

Molenaar

Swanson

et al. 2012

Animal

View full text Add to dashboard Cite

A potential role for epigenetic mechanisms in the regulation of mammary function in the dairy cow is emerging. Epigenetics is the study of heritable changes in genome function that occur because of chemical changes rather than DNA sequence changes. DNA methylation is an epigenetic event that results in the silencing of gene expression and may be passed on to the next generation. However, recent studies investigating different physiological states and changes in milk protein gene expression suggest that DNA methylation may also play an acute, regulatory, role in gene transcription. This overview will highlight the role of DNA methylation in the silencing of milk protein gene expression during mastitis and mammary involution. Moreover, environmental factors such as nutrition may induce epigenetic modifications of gene expression. The current research investigating the possibility of in utero, hence cross-generational, epigenetic modifications in dairy cows will also be discussed. Understanding how the mammary gland responds to environmental cues provides a potential to enhance milk production not only of the dairy cow but also of her daughter.Keywords: epigenetics, DNA methylation, transgeneration, milk production, dairy cows ImplicationsEpigenetic regulation of gene expression is emerging as a hitherto unknown level of biological control. We will discuss how epigenetics may be part of the enormously complex regulatory pathways underpinning milk production. Not only may epigenetic regulation be directly involved in milk production of the mother ('acute epigenetics'), but it may also indirectly affect milk production in its offspring through transgenerational epigenetics, by effects on foetal development in utero. Gaining a clearer understanding of this level of regulatory control may lead to new insights in optimizing milk production not only in today's cows but also in future generations. IntroductionMilk production in dairy cows is influenced by numerous factors, including the environment (e.g. nutrition, photoperiod and heat stress), hormones, local factors within the mammary gland (e.g. autocrine, paracrine and homeostatic feedback systems), diseases (e.g. mastitis) and management practises (e.g. milking frequency). At the cellular level, these factors influence both the number and the activity of the mammary epithelial cells that synthesize milk. Multiple cell signalling pathways have been identified that play a role in regulating milk synthesis (Suchyta et al., 2003;Connor et al., 2008;Finucane et al., 2008;Singh et al., 2008). At the initiation of lactation, the rapid increase to peak milk yield following parturition is primarily because of an increase in mammary epithelial activity in response to milking. The gradual decline in milk production following peak lactation is anomalous to gradual involution and is predominantly a result of mammary epithelial loss via apoptosis (Wilde et al., 1997;Capuco et al., 2001). Microarray studies on rodent (Master et al., 2002;Clarkson et al., 2004;Stein et al., 2004) an...

show abstract

Neomorphic agouti mutations in obese yellow mice

Cited by 421 publications

References 33 publications

A natural allele of Nxf1 suppresses retrovirus insertional mutations

A natural allele of Nxf1 suppresses retrovirus insertional mutations

Unusual long target duplication by insertion of intracisternal A‐particle element in radiation‐induced acute myeloid leukemia cells in mouse

Epigenetics: a possible role in acute and transgenerational regulation of dairy cow milk production

Contact Info

Product

Resources

About