Disease relevance of NDN

• Human necdin gene (NDN) is maternally imprinted and located in Prader-Willi syndrome deletion region 15q11.2-q12 [1].
• In search of other cellular targets of necdin, we screened cDNA libraries from neurally differentiated murine embryonal carcinoma P19 cells and adult rat brain by the yeast two-hybrid assay [2].
• The region including entire MHD (amino acids 116-280) of necdin was required for its interaction with p53, while the regions amino acids 144-184 and 191-222 within the MHD were required for both the nuclear matrix targeting and the cell growth suppression of osteosarcoma SAOS-2 cells [3].
• Systematic screening for mutations in the human necdin gene (NDN): identification of two naturally occurring polymorphisms and association analysis in body weight regulation [4].

High impact information on NDN

• Moreover, we found that CpG-rich regions in SNURF-SNRPN and NDN, which in somatic tissues are methylated on the maternal allele, are hypomethylated in unfertilized human oocytes [5].
• The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region [6].
• A complete lack of NDN expression in PWS brain and fibroblasts indicates that the gene is expressed exclusively from the paternal allele in these tissues and suggests a possible role of this new gene in PWS [6].
• NDN displays several characteristics of an imprinted locus, including allelic DNA methylation and asynchronous DNA replication [6].
• By using a yeast two-hybrid method, we found that pre-IL-1 alpha binds necdin, a nuclear protein with growth suppressor activity [7].

Chemical compound and disease context of NDN

• We have now examined the epigenetic characteristics of NDN, a target gene of the chromosome 15q11-q13 Prader-Willi Syndrome IC, using sodium bisulfite sequencing to analyze DNA methylation and chromatin immunoprecipitation to analyze histone modifications [8].
• Here we demonstrate that thyroid hormone regulates the transcription of the Necdin gene, a developmentally regulated candidate gene for the genomic imprinting-associated neurobehavioural disorder, Prader-Willi syndrome [9].

Biological context of NDN

• We isolated an NDN homologous sequence from a human genomic DNA library [1].
• Characterization and chromosomal mapping of a human Necdin pseudogene [1].
• The information about the necdin pseudogene in the human genome will be useful for genetic studies on NDN-associated neurogenic disorders [1].
• Expression studies demonstrated that pre-IL-1 alpha associates with necdin in the nuclei of mammalian cell lines and regulates cell growth and collagen expression [7].
• Moreover, necdin overexpression potently inhibited adipocyte differentiation and cell cycle progression [10].

Anatomical context of NDN

• NDN is expressed exclusively from the paternally inherited allele in human fibroblasts [11].
• Furthermore, mutant mice lacking the paternal necdin allele showed a significant reduction in the differentiation of forebrain GABAergic neurons in vivo and in vitro [12].
• Magel2 distribution partially overlaps that of NDN:, with strong expression being detected in the central nervous system in mid-gestation mouse embryos by in situ hybridization [13].
• NEFA was widely distributed in mouse organs, whereas necdin was expressed predominantly in the brain and skeletal muscle [2].
• E2F4 expression was decreased by 10-fold in muscle and 2.5-fold in adipose tissue; necdin was identified in adipose tissue only and increased 1.8-fold after TZD treatment [10].

Associations of NDN with chemical compounds

• We also found that NDN lies in a domain of paternal allele-specific histone hyperacetylation that correlates with transcriptional state, and a domain of differential histone H3 lysine 4 di- and tri-methylation that persists independent of transcription [8].
• Necdin and E2F4 are modulated by rosiglitazone therapy in diabetic human adipose and muscle tissue [10].
• Necdin enhanced the cytoplasmic retention of NEFA-GFP and potentiated the effect of NEFA-GFP on caffeine-evoked elevation of cytosolic Ca(2+) levels [2].
• Thyroid hormone-mediated negative transcriptional regulation of Necdin expression [9].

Physical interactions of NDN

• The necdin-binding site of hnRNP U was located near a carboxyl-terminal region that mediated the association between hnRNP U and the nuclear matrix [14].

Regulatory relationships of NDN

• The necdin gene is expressed predominantly in postmitotic neurons and encodes a growth suppressor that interacts with the transcription factors E2F1 and p53 [1].
• Based on these findings, we propose that the constitutively up-regulated expression of pre-IL-1 alpha in the nuclei of SSc fibroblasts up-regulates proliferation and matrix production of SSc fibroblasts through binding necdin, and by counteracting its effects on cell growth and collagen production [7].
• These results suggest that necdin suppresses cell proliferation through its interaction with hnRNP U in the specific subnuclear structure [14].

Other interactions of NDN

• SNRPN and NDN retained monoallelic expression in all the cancers examined [15].
• We isolated cDNA encoding full-length mouse hnRNP U to analyze its physical and functional interactions with necdin [14].
• We observed a bias towards maternal allele-specific DNA hypermethylation of the promoter CpG island of NDN, independent of tissue-specific transcriptional activity [8].
• The first domain is homologous among MAGE family members with a CT expression, but unique for each member of the MAGE-D and necdin families [16].
• Necdin acts as a cell cycle regulatory protein and plays a key role in the pathogenesis of Prader-Willi syndrome, a neurogenetic disorder [17].

Analytical, diagnostic and therapeutic context of NDN

• Necdin significantly increased the populations of cells expressing the GABAergic neuron markers calbindin D-28k and glutamic acid decarboxylase when overexpressed by electroporation in cultured forebrain slices [12].
• The orthologous mouse gene (Magel2) is located within 150 kb of NDN:, is imprinted with paternal-only expression and is expressed predominantly in late developmental stages and adult brain as shown by northern blotting, RT-PCR and whole-mount RNA in situ hybridization [13].
• We have now examined the chromatin accessibility of the promoter region of one of the Imprinting Centre-controlled genes, NDN encoding necdin, using in vivo DNA footprinting to identify sites of DNA-protein interaction and altered chromatin configuration [18].

References