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Cited by 137Neurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene RegulationCongenital heart defects research

Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling

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Hämmerle, Barbara, Ulin, Edgar, Guimera, Jordi, Becker, Walter, Guillemot, François, Tejedor, Francisco J.·2011·Development
DOI 10.1242/dev.066167PMC PMC3100710
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Abstract

The decision of a neural precursor to stop dividing and begin its terminal differentiation at the correct place, and at the right time, is a crucial step in the generation of cell diversity in the nervous system. Here, we show that the Down's syndrome candidate gene (Mnb/Dyrk1a) is transiently expressed in prospective neurons of vertebrate CNS neuroepithelia. The gain of function (GoF) of Mnb/Dyrk1a induced proliferation arrest. Conversely, its loss of function (LoF) caused over proliferation and cell death. We found that MNB/DYRK1A is both necessary and sufficient to upregulate, at transcriptional level, the expression of the cyclin-dependent kinase inhibitor p27KIP1 in the embryonic chick spinal cord and mouse telencephalon, supporting a regulatory role for MNB/DYRK1A in cell cycle exit of vertebrate CNS neurons. All these actions required the kinase activity of MNB/DYRK1A. We also observed that MNB/DYRK1A is co-expressed with the NOTCH ligand Delta1 in single neuronal precursors. Furthermore, we found that MNB/DYRK1A suppressed NOTCH signaling, counteracted the pro-proliferative action of the NOTCH intracellular domain (NICD), stimulated Delta1 expression and was required for the neuronal differentiation induced by the decrease in NOTCH signaling. Nevertheless, although Mnb/Dyrk1a GoF led to extensive withdrawal of neuronal precursors from the cell cycle, it was insufficient to elicit their differentiation. Remarkably, a transient (ON/OFF) Mnb/Dyrk1a GoF efficiently induced neuronal differentiation. We propose that the transient expression of MNB/DYRK1A in neuronal precursors acts as a binary switch, coupling the end of proliferation and the initiation of neuronal differentiation by upregulating p27KIP1 expression and suppressing NOTCH signaling.

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  • Transient expression of Dyrk1a could promote cell cycle exit, and its subsequent downregulation allows cells to undergo neuronal differentiation.

    “Thus, the transient expression of Dyrk1a could promote cell cycle exit, and its subsequent down regulation allows cells to undergo neuronal differentiation (Hammerle et al., 2008; Hammerle et al., 2011).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Hammerle et al., 2011

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References 92 · Cited by 137

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Authors
Hämmerle, B., Ulin, E., Guimera, J., Becker, W., Guillemot, F., & Tejedor, F. J.
Affiliations
  • Instituto de Neurociencias, CSIC and Universidad Miguel Hernandez, Alicante 03550, Spain
  • Instituto de Neurociencias (ES)
  • HMGU-Institute of Developmental Genetics, 85764 Munich, Germany
  • RWTH Aachen University (DE)
  • Division of Molecular Neurobiology, National Institute for Medical Research, London NW7 1AA, UK
Corresponding author
Tejedor, Francisco J.
ORCID
Venue
Development
Publisher
The Company of Biologists
Published
2011-06-15
Volume
138
Issue
12
Pages
2543-2554
ISSN
  • 0950-1991 (ISSN-L)
  • 1477-9129
DOI
10.1242/dev.066167
PMC
PMC3100710
OpenAlex
W2060241396
Cited by
137
References
92
Citations by year
2026: 7 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 13 · 2020: 8 · 2019: 8 · 2018: 10 · 2017: 7 · 2016: 18 · 2015: 10 · 2014: 8 · 2013: 9 · 2012: 10
FWCI
2.94
Type
journal article
Language
en
Open access
Locations
  • Development (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
DYRK1A, p27, Notch signaling, neuronal differentiation, cell cycle exit, neuronal precursors, Delta1, cyclin-dependent kinase inhibitors, transient expression, Down syndrome, neural progenitor proliferation, telencephalon, spinal cord, kinase activity
MeSH terms
Dyrk Kinases, Animals, Cell Cycle, Cell Differentiation, Chickens, Drosophila melanogaster, Protein-Tyrosine Kinases, Signal Transduction, Transcriptional Activation, PC12 Cells, Protein Serine-Threonine Kinases, Drosophila Proteins, Cyclin-Dependent Kinase Inhibitor p27, Rats, Receptors, Notch, Neural Stem Cells

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