Notch-Delta signaling regulates many developmental processes, including tissue homeostasis, and maintenance of stem cells. Upon interaction of juxtaposed cells via Notch and Delta proteins, intracellular domains of both transmembrane proteins are cleaved and translocate to the nucleus. Notch intracellular domain activates target gene expression; however, the role of the Delta intracellular domain remains elusive. Here, we show the biological function of Delta like 1 intracellular domain (D1ICD) by modulating its production. We find the sustained production of D1ICD abrogates cell proliferation but enhances neurogenesis in the developing dorsal root ganglia (DRG), whereas inhibition of D1ICD production promotes cell proliferation and gliogenesis. D1ICD acts as an integral component of lateral inhibition mechanism by inhibiting Notch activity. In addition, D1ICD promotes neurogenesis through a Notch signaling independent manner. We show that D1ICD binds to Erk1/2 in neural crest stem cells, and inhibits the phosphorylation of Erk1/2. In summary, our results indicate that D1ICD regulates DRG development via modulating not only Notch signaling but also the MAP kinase pathway.
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RESEARCH ARTICLE|
14 September 2021
Cleaved Delta like 1 intracellular domain regulates neural development via Notch signal dependent and independent pathways
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Neural development
Yusuke Okubo
,
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
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Fumiaki Ohtake,
Fumiaki Ohtake
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
2
Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501
, Japan
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Katsuhide Igarashi,
Katsuhide Igarashi
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
3
Life Science Tokyo Advanced Research center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Science, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501
, Japan
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Yukuto Yasuhiko,
Yukuto Yasuhiko
#
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
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Yoko Hirabayashi,
Yoko Hirabayashi
#
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
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Yumiko Saga,
Yumiko Saga
*
4
Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima 411-8540
, Japan
5
Department of Biological Science, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033
, Japan
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1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
Fumiaki Ohtake
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
2
Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501
, Japan
Katsuhide Igarashi
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
3
Life Science Tokyo Advanced Research center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Science, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501
, Japan
Yukuto Yasuhiko
#
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
Yoko Hirabayashi
#
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
Yumiko Saga
*
4
Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima 411-8540
, Japan
5
Department of Biological Science, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033
, Japan
Jun Kanno
#
1
Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501
, Japan
#
Present address: Division of Cellular and Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 3-25-26, Kawasaki-ku Tonomachi, Kawasaki, Kanagawa 210-9501, Japan
Received:
04 Jun 2020
Accepted:
06 Sep 2021
Online ISSN: 1477-9129
Print ISSN: 0950-1991
Funding Group:
- Award Group:
- Funder(s): Japan Society for the Promotion of Science
- Award Id(s): 25840096
- Funder(s):
Funding Group:
- Award Group:
- Funder(s): Takeda Science Foundation
- Funder(s):
© 2021. Published by The Company of Biologists Ltd
2021
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Development dev.193664.
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Received:
04 Jun 2020
Accepted:
06 Sep 2021
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Yusuke Okubo, Fumiaki Ohtake, Katsuhide Igarashi, Yukuto Yasuhiko, Yoko Hirabayashi, Yumiko Saga, Jun Kanno; Cleaved Delta like 1 intracellular domain regulates neural development via Notch signal dependent and independent pathways. Development 2021; dev.193664. doi: https://doi.org/10.1242/dev.193664
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