Evidence for genetic modifiers of postnatal lethality in PWS-IC deletion mice

Chamberlain, Stormy J.; Johnstone, Karen A.; DuBose, Amanda J.; Simon, Tom; Bartolomei, Marisa S.; Resnick, James L.; Brannan, Camilynn I.

doi:10.1093/hmg/ddh314

Cited by 51 publications

(43 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The only significant alteration in PWS gene expression is a reduction in Snrpn and the snoRNAs, and an increase in paternal expression of Ube3a. In this regard, these animals resemble other models lacking expression of the Snrpn transcription unit as a result of a germline deletion of the PWS-IC or a deletion spanning from Snrpn to Ube3a (18,33,34). In the present PWS-IC flox model, the Snrpn U exons drive expression of all of the downstream cluster gene products indicating that the upstream exons are not exclusively dedicated to a particular processing variant.…”

Section: Discussionsupporting

confidence: 51%

Temporal and developmental requirements for the Prader–Willi imprinting center

DuBose

Smith²,

Johnstone³

et al. 2012

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

Self Cite

View full text Add to dashboard Cite

Imprinted gene expression associated with Prader-Willi syndrome (PWS) and Angelman syndrome (AS) is controlled by two imprinting centers (ICs), the PWS-IC and the AS-IC. The PWS-IC operates in cis to activate transcription of genes that are expressed exclusively from the paternal allele. We have created a conditional allele of the PWS-IC to investigate its developmental activity. Deletion of the paternal PWS-IC in the embryo before implantation abolishes expression of the paternal-only genes in the neonatal brain. Surprisingly, deletion of the PWS-IC in early brain progenitors does not affect the subsequent imprinted status of PWS/AS genes in the newborn brain. These results indicate that the PWS-IC functions to protect the paternal epigenotype at the epiblast stage of development but is dispensable thereafter.

show abstract

Section: Discussionsupporting

confidence: 51%

Temporal and developmental requirements for the Prader–Willi imprinting center

DuBose

Smith²,

Johnstone³

et al. 2012

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Given this surprising result, which corroborates previous reports in younger mice with IC deletions (Yang et al . 1998, Chamberlain et al . 2004), we examined the aetiology of this leanness, quantifying indices of energy intake, storage and utilisation.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical leanness in the imprinting-centre deletion mouse model for Prader–Willi syndrome

Golding

Rees

Davies

et al. 2017

Journal of Endocrinology

View full text Add to dashboard Cite

Prader–Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 15q11–q13, is characterised by growth retardation, hyperphagia and obesity. However, as single gene mutation mouse models for this condition display an incomplete spectrum of the PWS phenotype, we have characterised the metabolic impairment in a mouse model for ‘full’ PWS, in which deletion of the imprinting centre (IC) abolishes paternal gene expression from the entire PWS cluster. We show that PWS-ICdel mice displayed postnatal growth retardation, with reduced body weight, hyperghrelinaemia and marked abdominal leanness; proportionate retroperitoneal, epididymal/omental and inguinal white adipose tissue (WAT) weights being reduced by 82%, 84% and 67%, respectively. PWS-ICdel mice also displayed a 48% reduction in proportionate interscapular brown adipose tissue (isBAT) weight with significant ‘beiging’ of abdominal WAT, and a 2°C increase in interscapular surface body temperature. Maintenance of PWS-ICdel mice under thermoneutral conditions (30°C) suppressed the thermogenic activity in PWS-ICdel males, but failed to elevate the abdominal WAT weight, possibly due to a normalisation of caloric intake. Interestingly, PWS-ICdel mice also showed exaggerated food hoarding behaviour with standard and high-fat diets, but despite becoming hyperphagic when switched to a high-fat diet, PWS-ICdel mice failed to gain weight. This evidence indicates that, unlike humans with PWS, loss of paternal gene expression from the PWS cluster in mice results in abdominal leanness. Although reduced subcutaneous insulation may lead to exaggerated heat loss and thermogenesis, abdominal leanness is likely to arise from a reduced lipid storage capacity rather than increased energy utilisation in BAT.

show abstract

“…Despite these genetic insights, considerable controversy due to the variable penetrance of PWS remains, with patient studies indicating that deletions, including those of MAGEL2 and NDN , may not be sufficient to cause disease (92). These conflicting results may be explained by interactions of PWS genes with maternally derived genetic modifiers (93), although the relevant genetic variants remain unidentified.…”

Section: Disorders That Disrupt Development Of Central Feeding Circuitrymentioning

confidence: 99%

Feed Your Head: Neurodevelopmental Control of Feeding and Metabolism

Lee

Blackshaw

2014

Annu. Rev. Physiol.

View full text Add to dashboard Cite

During critical periods of development early in life, excessive or scarce nutritional environments can disrupt the development of central feeding and metabolic neural circuitry, leading to obesity and metabolic disorders in adulthood. A better understanding of the genetic networks that control the development of feeding and metabolic neural circuits, along with knowledge of how and where dietary signals disrupt this process, can serve as the basis for future therapies aimed at reversing the public health crisis that is now building as a result of the global obesity epidemic. This review of animal and human studies highlights recent insights into the molecular mechanisms that regulate the development of central feeding circuitries, the mechanisms by which gestational and early postnatal nutritional status affects this process, and approaches aimed at counteracting the deleterious effects of early over- and underfeeding.

show abstract

Evidence for genetic modifiers of postnatal lethality in PWS-IC deletion mice

Cited by 51 publications

References 37 publications

Temporal and developmental requirements for the Prader–Willi imprinting center

Temporal and developmental requirements for the Prader–Willi imprinting center

Paradoxical leanness in the imprinting-centre deletion mouse model for Prader–Willi syndrome

Feed Your Head: Neurodevelopmental Control of Feeding and Metabolism

Contact Info

Product

Resources

About