Journal
DEVELOPMENT
Volume 138, Issue 12, Pages 2543-2554Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.066167
Keywords
Neurogenesis; Neural proliferation; Neuronal differentiation; Down's syndrome; Mouse; Chick
Categories
Funding
- Deutsche Forschungsgemeinschaft [BE 1967/2-1, SFB-870]
- Medical Research Council [U117570528]
- Spanish Ministry of Science and Innovation
- Generalitat Valenciana
- Fundacion Inocente Inocente
- Fondation Jerome Lejeune
- MRC [MC_U117570528] Funding Source: UKRI
- Medical Research Council [MC_U117570528] Funding Source: researchfish
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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 p27(KIP1) 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 p27(KIP1) expression and suppressing NOTCH signaling.
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