Necdin Controls Proliferation and Apoptosis of Embryonic Neural Stem Cells in an Oxygen Tension-Dependent Manner

Huang, Zhenyu; Fujiwara, Kazushiro; Minamide, Ryohei; Hasegawa, Koichi; Yoshikawa, Kunio

doi:10.1523/jneurosci.5682-12.2013

Cited by 24 publications

(29 citation statements)

References 55 publications

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“…Expression vectors for mouse p53, necdin, and their deletion mutants were constructed as described [5], [48]. cDNAs for mouse MAGED1, necdin-like2 and MAGEL2 were cloned as described [4], [56].…”

Section: Methodsmentioning

confidence: 99%

Necdin Promotes Ubiquitin-Dependent Degradation of PIAS1 SUMO E3 Ligase

et al. 2014

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Necdin, a pleiotropic protein that promotes differentiation and survival of mammalian neurons, is a member of MAGE (melanoma antigen) family proteins that share a highly conserved MAGE homology domain. Several MAGE proteins interact with ubiquitin E3 ligases and modulate their activities. However, it remains unknown whether MAGE family proteins interact with SUMO (small ubiquitin-like modifier) E3 ligases such as PIAS (protein inhibitor of activated STAT) family, Nsmce2/Mms21 and Cbx4/Pc2. In the present study, we examined whether necdin interacts with these SUMO E3 ligases. Co-immunoprecipitation analysis revealed that necdin, MAGED1, MAGEF1 and MAGEL2 bound to PIAS1 but not to Nsmce2 or Cbx4. These SUMO E3 ligases bound to MAGEA1 but failed to interact with necdin-like 2/MAGEG1. Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination. Both PIAS1 and necdin were associated with the nuclear matrix, where the PIAS1 terminal deletion mutants failed to localize, implying that the nuclear matrix is indispensable for necdin-dependent ubiquitination of PIAS1. Our data suggest that necdin suppresses PIAS1 both by inhibiting SUMO E3 ligase activity and by promoting ubiquitin-dependent degradation.

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Section: Methodsmentioning

confidence: 99%

Necdin Promotes Ubiquitin-Dependent Degradation of PIAS1 SUMO E3 Ligase

et al. 2014

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“…Ndn plays an important role in proliferation and apoptosis of NSCs and in neuronal development and terminally differentiated neurons. [11][12][13] Embryo development requires proper expression of both maternally and paternally imprinted genes. Although uniparental embryos are not capable of full-term development due to defects in genomic imprinting, androgenetic ESCs and gPS cells can generate normal chimeras.…”

Section: Derivation Of Nscs From Gps Cellsmentioning

confidence: 99%

Epigenetic alteration of imprinted genes during neural differentiation of germline-derived pluripotent stem cells

et al. 2016

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Spermatogonial stem cells (SSCs), which are unipotent stem cells in the testes that give rise to sperm, can be converted into germline-derived pluripotent stem (gPS) by self-induction. The androgenetic imprinting pattern of SSCs is maintained even after their reprogramming into gPS cells. In this study, we used an in vitro neural differentiation model to investigate whether the imprinting patterns are maintained or altered during differentiation. The androgenetic patterns of H19, Snrpn, and Mest were maintained even after differentiation of gPS cells into NSCs (gPS-NSCs), whereas the fully unmethylated status of Ndn in SSCs was altered to somatic patterns in gPS cells and gPS-NSCs. Thus, our study demonstrates epigenetic alteration of genomic imprinting during the induction of pluripotency in SSCs and neural differentiation, suggesting that gPS-NSCs can be a useful model to study the roles of imprinted genes in brain development and human neurodevelopmental disorders.

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“…Necdin modulates sumoylation and ubiquitination of its target proteins (Huang et al . ; Gur et al . ; Hasegawa et al .…”

Section: Resultsmentioning

confidence: 99%

Terminal differentiation of cortical neurons rapidly remodels RanGAP‐mediated nuclear transport system

et al. 2016

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Terminal differentiation of neurons is accompanied by irreversible exit from the cell cycle and expression of neuronal phenotypes. The molecular mechanism whereby committed neuronal progenitors lose their ability to reenter the cell cycle is largely unknown. Here, we report that the nuclear transport system is rapidly remodeled in primary cortical progenitor cells (CPCs) at the very beginning of neuronal terminal differentiation. High levels of Ran GTPase‐activating protein 1 (RanGAP), a key regulator of the Ran GTP‐GDP cycle, in primary CPCs are drastically reduced upon neuronal induction. Small ubiquitin‐like modifier (SUMO)‐2/3‐conjugated RanGAP undergoes desumoylation and degradation in neuronally committed CPCs, where reduced RanGAP levels impede the nuclear import of nucleocytoplasmic shuttling proteins including the DNA replication initiation factor Cdc6. Furthermore, RNAi‐mediated down‐regulation of RanGAP expression in undifferentiated CPCs induces neuronal phenotypes including cell cycle exit. Our data suggest that remodeling of the RanGAP‐mediated nuclear transport system plays a key role in cell cycle exit for terminal differentiation of cortical neurons.

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Necdin Controls Proliferation and Apoptosis of Embryonic Neural Stem Cells in an Oxygen Tension-Dependent Manner

Cited by 24 publications

References 55 publications

Necdin Promotes Ubiquitin-Dependent Degradation of PIAS1 SUMO E3 Ligase

Necdin Promotes Ubiquitin-Dependent Degradation of PIAS1 SUMO E3 Ligase

Epigenetic alteration of imprinted genes during neural differentiation of germline-derived pluripotent stem cells

Terminal differentiation of cortical neurons rapidly remodels RanGAP‐mediated nuclear transport system

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