Necdin-deficient mice do not show lethality or the obesity and infertility of Prader-Willi syndrome

Tsai, Ting-Fen; Armstrong, Dawna L.; Beaudet, Arthur L.

doi:10.1038/8722

Cited by 81 publications

(44 citation statements)

References 15 publications

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“…We speculate that these necdinhomologous proteins compensate for the absence of necdin expression in Prader-Willi syndrome and necdin knockout mice. This idea may account for the inconsistent phenotypes seen in necdin knockout mice (18,19,46,47). Further studies on necdin-homologous MAGE proteins will provide valuable insights into the roles of these family proteins in brain development and neurodevelopmental disorders.…”

Section: Discussionmentioning

confidence: 99%

Necdin-related MAGE Proteins Differentially Interact with the E2F1 Transcription Factor and the p75 Neurotrophin Receptor

Kuwako

Taniura

Yoshikawa

2004

Journal of Biological Chemistry

118

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Necdin is a growth suppressor expressed predominantly in postmitotic neurons and implicated in their terminal differentiation. Necdin shows a moderate homology to the MAGE family proteins, the functional roles of which are largely unknown. Human genes encoding necdin, MAGEL2 (necdin-like 1), and MAGE-G1 (necdin-like 2) are located in proximal chromosome 15q, a region associated with neurodevelopmental disorders such as Prader-Willi syndrome, Angelman syndrome, and autistic disorder. The necdin and MAGEL2 genes are subjected to genomic imprinting and suggested to be involved in the etiology of Prader-Willi syndrome. In this study, we compared biochemical and functional characteristics of murine orthologs of these necdin-related MAGE proteins. The colony formation and bromodeoxyuridine incorporation analyses revealed that necdin and MAGE-G1, but not MAGEL2, induced growth arrest. Necdin and MAGE-G1 interacted with the transcription factor E2F1 via its transactivation domain, repressed E2F1-dependent transcription, and antagonized E2F1-induced apoptosis of N1E-115 neuroblastoma cells. In addition, necdin and MAGE-G1 interacted with the p75 neurotrophin receptor via its distinct intracellular domains. In contrast, MAGEL2 failed to bind to these necdin interactors, suggesting that MAGEL2 has no necdin-like function in developing brain. Overexpression of p75 translocated necdin and MAGE-G1 in the proximity of the plasma membrane and reduced their association with E2F1 to facilitate E2F1-induced death of neuroblastoma cells. These results suggest that necdin and MAGE-G1 target both E2F1 and p75 to regulate cell viability during brain development.

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Section: Discussionmentioning

confidence: 99%

Necdin-related MAGE Proteins Differentially Interact with the E2F1 Transcription Factor and the p75 Neurotrophin Receptor

Kuwako

Taniura

Yoshikawa

2004

Journal of Biological Chemistry

118

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“…We predicted that if a gamete-specific methylation imprint exists in Ndn, then the 5Ј CpG island represents the most probable location for the imprint. This prediction is based on two recent gene-targeting experiments that created null mutations of Ndn in the mouse (12,35). In both cases, the lacZ gene replaced the Ndn gene starting at the BamHI site located between CpG positions 23 and 24 ( Fig.…”

Section: Identification Of Repetitive Elements In Cpg-rich Regionsmentioning

confidence: 99%

Establishment and Maintenance of DNA Methylation Patterns in Mouse Ndn: Implications for Maintenance of Imprinting in Target Genes of the Imprinting Center

Hanel

Wevrick

2001

Molecular and Cellular Biology

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Ndn is located on chromosome 7C, an imprinted region of the mouse genome. Imprinting of Ndn and adjacent paternally expressed genes is regulated by a regional imprinting control element known as the imprinting center (IC). An IC also controls imprint resetting of target genes in the region of conserved synteny on human chromosome 15q11-q13, which is deleted or rearranged in the neurodevelopmental disorder PraderWilli syndrome. Epigenetic modifications such as DNA methylation, which occur in gametes and can be stably propagated, are presumed to establish and maintain the imprint in target genes of the IC. While most DNA becomes substantially demethylated by the blastocyst stage, some imprinted genes have regions that escape global demethylation and may maintain the imprint. We have now analyzed the methylation of 39 CpG dinucleotide sequences in the 5 end of Ndn by sodium bisulfite sequencing in gametes and in preimplantation and adult tissues. While sperm DNA is completely unmethylated across this region, oocyte DNA is partially methylated. A distinctive but unstable maternal methylation pattern persists until the morula stage and is lost in the blastocyst stage, where low levels of methylation are present on most DNA strands of either parental origin. The methylation pattern is then substantially remodeled, and fewer than half of maternally derived DNA strands in adult brain resemble the oocyte pattern. We postulate that for Ndn, DNA methylation may initially preserve a gametic imprint during preimplantation development, but other epigenetic events may maintain the imprint later in embryonic development.

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“…Mechanisms involved are: deletion in 70–75% of patients, maternal uniparental disomy in 20–25%, imprinting center mutations in 2–5%, and 1% have structural abnormalities (translocations) involving this critical region [6, 7]. However, the only identified protein products at these loci are those for the SNRPN and ZNF127 genes, hence the precise cause of PWS is still unknown [8,9,10]. …”

Section: Introductionmentioning

confidence: 99%

Adrenarche in Prader-Willi Syndrome Appears Not Related to Insulin Sensitivity and Serum Adiponectin

Unanue¹,

Bazaes²,

Íñiguez³

et al. 2006

Horm Res Paediatr

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Prader-Willi syndrome (PWS) is a genetic disorder characterized by dysmorphic features, obesity, hypogonadism, hypotonia and mental retardation. Obesity has been linked to insulin resistance and the latter has also been associated with premature adrenarche. Since up to date a controlled study to investigate adrenarche and its hormonal regulation was lacking in PWS, our aim was to assess whether prepubertal PWS patients develop premature adrenarche and its relationship with markers of insulin sensitivity. Fourteen prepubertal children with PWS (6 M, 8 F) and 10 non-syndromal simple obese matched controls (5 M, 5 F) participated (mean age: 7.62 ± 1.84 years). A fasting blood sample was obtained for adrenal and ovarian androgens, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-1, leptin, adiponectin and a lipid profile. Thereafter an oral glucose tolerance test was performed. PWS patients were smaller at birth and a higher proportion displayed premature pubarche. No differences were found in testosterone, androstenedione, sex hormone binding globulin, free androgen index, homeostatic model assessment-IR, 2-hour insulin, leptin or adiponectin levels. 17-hydroxyprogesterone and DHEAS levels however, were significantly higher in PWS. IGF-I levels were significantly lower in PWS and correlated significantly with height SDS (p < 0.05). In conclusion, a higher proportion of premature adrenarche in our PW patients was observed, which was not explained by differences in insulin sensitivity or plasma levels of adipokines and IGF-I.

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Necdin-deficient mice do not show lethality or the obesity and infertility of Prader-Willi syndrome

Cited by 81 publications

References 15 publications

Necdin-related MAGE Proteins Differentially Interact with the E2F1 Transcription Factor and the p75 Neurotrophin Receptor

Necdin-related MAGE Proteins Differentially Interact with the E2F1 Transcription Factor and the p75 Neurotrophin Receptor

Establishment and Maintenance of DNA Methylation Patterns in Mouse Ndn: Implications for Maintenance of Imprinting in Target Genes of the Imprinting Center

Adrenarche in Prader-Willi Syndrome Appears Not Related to Insulin Sensitivity and Serum Adiponectin

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