A novel brain-specific mRNA encoding nuclear protein (necdin) expressed in neurally differentiated embryonal carcinoma cells

Maruyama, Kei; Usami, Mihoko; Aizawa, Takako; Yoshikawa, Kunio

doi:10.1016/0006-291x(91)91812-q

Cited by 144 publications

(123 citation statements)

References 8 publications

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“…Necdin is initially characterized as a nuclear protein (1,2) and is partly associated with the nuclear matrix (28). Necdin binds to the typical nuclear proteins E2F and p53 (11,12).…”

Section: E2f1 Abrogates Necdin-induced Growth Arrest Of N1e-115 Cellsmentioning

confidence: 99%

“…Necdin is a 325-amino acid protein encoded in a cDNA sequence that has been isolated from a subtraction library of neurally differentiated mouse embryonal carcinoma P19 cells (1). The necdin gene is expressed in most of the terminally differentiated neurons, although its expression levels vary among neuronal cell types, being the highest in the hypothalamus and brain stem (2,3).…”

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confidence: 99%

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Ectopic Expression of Necdin Induces Differentiation of Mouse Neuroblastoma Cells

Kobayashi

Taniura

Yoshikawa

2002

Journal of Biological Chemistry

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Necdin is expressed predominantly in postmitotic neurons, and ectopic expression of this protein strongly suppresses cell growth. Necdin has been implicated in the pathogenesis of Prader-Willi syndrome, a human neurodevelopmental disorder associated with genomic imprinting. Here we demonstrate that ectopic expression of necdin induces a neuronal phenotype in neuroblastoma cells. Necdin was undetectable in mouse neuroblastoma N1E-115 cells under undifferentiated and differentiated conditions. N1E-115 cells transfected with necdin cDNA showed morphological differentiation such as neurite outgrowth and expression of the synaptic marker proteins synaptotagmin and synaptophysin. In addition, Western blot analysis of the retinoblastoma protein (Rb) family members Rb, p130, and p107 revealed that necdin cDNA transfectants contained an increased level of p130 and a reduced level of p107, a pattern seen in differentiated G 0 cells. The transcription factors E2F1 and E2F4 physically interacted with necdin via their carboxyl-terminal transactivation domains, but only E2F1 abrogated necdin-induced growth arrest and neurite outgrowth of neuroblastoma cells. Overexpression of E2F1 in differentiated N1E-115 cells induced apoptosis, which was antagonized by co-expression of necdin. These results suggest that necdin promotes the differentiation and survival of neurons through its antagonistic interactions with E2F1.Necdin is a 325-amino acid protein encoded in a cDNA sequence that has been isolated from a subtraction library of neurally differentiated mouse embryonal carcinoma P19 cells (1). The necdin gene is expressed in most of the terminally differentiated neurons, although its expression levels vary among neuronal cell types, being the highest in the hypothalamus and brain stem (2, 3). The human necdin gene is mapped to chromosome 15q11.2-q12, a region deleted in Prader-Willi syndrome (PWS) 1 (4 -6). PWS is a neurodevelopmental disorder associated with genomic imprinting, and its major symptoms such as feeding problems, gross obesity, and hypogonadism are consistent with a hypothalamic defect. Human and mouse necdin genes are maternally imprinted and transcribed only from the paternal allele (4, 5, 7). Necdin is not expressed in the cells prepared from PWS patients whose chromosome 15q11.2-q13 region in the paternal allele is deleted. Disruption of the paternal allele of mouse necdin gene results in early postnatal lethality (8), reduction in specific hypothalamic neurons such as luteinizing hormone-releasing hormone-and oxytocin-containing neurons, and behavioral alternations, which are reminiscent of human PWS (9). Therefore, it is likely that a defect in necdin expression is responsible, at least in part, for various clinical symptoms of PWS. However, little is known about the functional roles of necdin in neuronal differentiation and development.Accumulating evidence has suggested that necdin is a growth suppressor expressed in terminally differentiated cells. Ectopic expression of necdin suppresses the proliferation of...

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“…Necdin is initially characterized as a nuclear protein (1,2) and is partly associated with the nuclear matrix (28). Necdin binds to the typical nuclear proteins E2F and p53 (11,12).…”

Section: E2f1 Abrogates Necdin-induced Growth Arrest Of N1e-115 Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

Ectopic Expression of Necdin Induces Differentiation of Mouse Neuroblastoma Cells

Kobayashi

Taniura

Yoshikawa

2002

Journal of Biological Chemistry

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“…Necdin is a 325 aa residue protein expressed in terminally differentiated neurons (Maruyama et al, 1991;Aizawa et al, 1992;Uetsuki et al, 1996;Kuwajima et al, 2004). Necdin strongly suppresses the proliferation of several cell lines (Hayashi et al, 1995;Taniura et al, 1998) and interacts with cell cycle regulatory transcription factors E2F1 and E2F4 Kobayashi et al, 2002), which are also the targets of retinoblastoma tumor suppressor protein (Rb) (Nevins, 1992).…”

Section: Introductionmentioning

confidence: 99%

Disruption of the Paternal Necdin Gene Diminishes TrkA Signaling for Sensory Neuron Survival

Kuwako¹,

Hosokawa²,

Nishimura³

et al. 2005

J. Neurosci.

120

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Necdin is a multifunctional signaling protein that stabilizes terminal differentiation of postmitotic neurons. The human necdin gene in chromosome 15q11-q12 is maternally imprinted, paternally transcribed, and not expressed in Prader-Willi syndrome, a human genomic imprinting-associated neurodevelopmental disorder. Although necdin-deficient mice display several abnormal phenotypes reminiscent of this syndrome, little is known about molecular mechanisms that lead to the neurodevelopmental defects. Here, we demonstrate that paternally expressed necdin is required for physiological development of nerve growth factor (NGF)-dependent sensory neurons. Mouse embryos defective in the paternal necdin allele displayed absent necdin expression in the dorsal root ganglia, in which the tropomyosin-related kinase A (TrkA) receptor tyrosine kinase and the p75 neurotrophin receptor were expressed in a normal manner. Necdin interacted with both TrkA and p75 to facilitate the association between these receptors. NGF-induced phosphorylation of TrkA and mitogen-activated protein kinase was significantly diminished in the necdin-null sensory ganglia. Furthermore, the mice lacking the paternal necdin allele displayed augmented apoptosis in the sensory ganglia in vivo and had a reduced population of substance P-containing neurons. These mutant mice showed significantly high tolerance to thermal pain, which is often seen in individuals with Prader-Willi syndrome. These results suggest that paternally expressed necdin facilitates TrkA signaling to promote the survival of NGF-dependent nociceptive neurons.

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“…Necdin is a potent mitotic suppressor that is expressed predominantly in postmitotic neurons (Maruyama et al, 1991;Aizawa et al, 1992;Hayashi et al, 1995;Uetsuki et al, 1996). Necdin, like Rb, targets E2F1 and represses E2F1-dependent transcription in osteosarcoma cells Kuwako et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis

Kurita

Kuwajima²,

Nishimura³

et al. 2006

J. Neurosci.

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The cell cycle-regulatory transcription factor E2F1 induces apoptosis of postmitotic neurons in developmental and pathological situations. E2F1 transcriptionally activates many proapoptotic genes including the cyclin-dependent protein kinase cell division cycle 2 (Cdc2). Necdin is a potent mitotic suppressor expressed predominantly in postmitotic neurons and interacts with E2F1 to suppress E2F1-mediated gene transcription. The necdin gene NDN is maternally imprinted and expressed only from the paternal allele. Deletion of the paternal NDN is implicated in the pathogenesis of Prader-Willi syndrome, a genomic imprinting-associated neurodevelopmental disorder. Here, we show that paternally expressed necdin represses E2F1-dependent cdc2 gene transcription and attenuates apoptosis of postmitotic neurons. Necdin was abundantly expressed in differentiated cerebellar granule neurons (CGNs). Neuronal activity deprivation elevated the expression of both E2F1 and Cdc2 in primary CGNs prepared from mice at postnatal day 6, whereas the necdin levels remained unchanged. In chromatin immunoprecipitation analysis, endogenous necdin was associated with the cdc2 promoter containing an E2F-binding site in activity-deprived CGNs. After activity deprivation, CGNs underwent apoptosis, which was augmented in those prepared from mice defective in the paternal Ndn allele (Ndn ϩm/Ϫp ). The levels of cdc2 mRNA, protein, and kinase activity were significantly higher in Ndn ϩm/Ϫp CGNs than in wild-type CGNs under activity-deprived conditions. Furthermore, the populations of Cdc2-immunoreactive and apoptotic cells were increased in the cerebellum in vivo of Ndn ϩm/Ϫp mice. These results suggest that endogenous necdin attenuates neuronal apoptosis by suppressing the E2F1-Cdc2 system.

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A novel brain-specific mRNA encoding nuclear protein (necdin) expressed in neurally differentiated embryonal carcinoma cells

Cited by 144 publications

References 8 publications

Ectopic Expression of Necdin Induces Differentiation of Mouse Neuroblastoma Cells

Ectopic Expression of Necdin Induces Differentiation of Mouse Neuroblastoma Cells

Disruption of the Paternal Necdin Gene Diminishes TrkA Signaling for Sensory Neuron Survival

Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis

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