Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells

Seiji Hitoshi; Yugo Ishino; Akhilesh Kumar; Salma Jasmine; Kenji F. Tanaka; Takeshi Kondo; Shigeaki Kato; Toshihiko Hosoya; Yoshiki Hotta; Kazuhiro Ikenaka

doi:10.1038/nn.2875

Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells

Seiji Hitoshi, Yugo Ishino, Akhilesh Kumar, Salma Jasmine, Kenji F. Tanaka, Takeshi Kondo, Shigeaki Kato, Toshihiko Hosoya, Yoshiki Hotta, Kazuhiro Ikenaka

Research output: Contribution to journal › Article › peer-review

50 Citations (Scopus)

Abstract

Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 anD₂) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1 ^-/-; Gcm2 ^-/- mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway.

Original language	English
Pages (from-to)	957-964
Number of pages	8
Journal	Nature Neuroscience
Volume	14
Issue number	8
DOIs	https://doi.org/10.1038/nn.2875
Publication status	Published - 2011 Aug
Externally published	Yes

ASJC Scopus subject areas

Neuroscience(all)

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@article{1b342cf9e9df489c85b7eb0e83a72067,

title = "Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells",

abstract = "Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 anD2) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1 -/-; Gcm2 -/- mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway.",

author = "Seiji Hitoshi and Yugo Ishino and Akhilesh Kumar and Salma Jasmine and Tanaka, {Kenji F.} and Takeshi Kondo and Shigeaki Kato and Toshihiko Hosoya and Yoshiki Hotta and Kazuhiro Ikenaka",

note = "Funding Information: We thank R. Kageyama, J.S. Nye, T. Miyazaki and T. Honjo for plasmids, T.-e.U and Y. Imai for MBD4 mutant mice, and R. Kageyama, D. van der Kooy and K. Nakashima for comments. This work was supported by a Grant-in-Aid for Exploratory Research (19650096) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (K.I.S.H.).",

year = "2011",

month = aug,

doi = "10.1038/nn.2875",

language = "English",

volume = "14",

pages = "957--964",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

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T1 - Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells

AU - Hitoshi, Seiji

AU - Ishino, Yugo

AU - Kumar, Akhilesh

AU - Jasmine, Salma

AU - Tanaka, Kenji F.

AU - Kondo, Takeshi

AU - Kato, Shigeaki

AU - Hosoya, Toshihiko

AU - Hotta, Yoshiki

AU - Ikenaka, Kazuhiro

N1 - Funding Information: We thank R. Kageyama, J.S. Nye, T. Miyazaki and T. Honjo for plasmids, T.-e.U and Y. Imai for MBD4 mutant mice, and R. Kageyama, D. van der Kooy and K. Nakashima for comments. This work was supported by a Grant-in-Aid for Exploratory Research (19650096) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (K.I.S.H.).

PY - 2011/8

Y1 - 2011/8

N2 - Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 anD2) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1 -/-; Gcm2 -/- mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway.

AB - Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 anD2) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1 -/-; Gcm2 -/- mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway.

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Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells

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