Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling
| Autor: | Walter Becker, Barbara Hämmerle, Edgar Ulin, François Guillemot, Jordi Guimera, Francisco J. Tejedor |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Transcriptional Activation
Programmed cell death Mouse Neurogenesis Cellular differentiation Chicks Notch signaling pathway Protein Serine-Threonine Kinases Biology PC12 Cells Down’s syndrome Neural Stem Cells Animals Drosophila Proteins Kinase activity Molecular Biology Research Articles Receptors Notch Cell Cycle Cell Differentiation Protein-Tyrosine Kinases Cell cycle Neural stem cell Rats Cell biology Drosophila melanogaster Neuronal differentiation Neural proliferation Signal transduction Chickens Cyclin-Dependent Kinase Inhibitor p27 Signal Transduction Developmental Biology |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.066167 |
| Popis: | 12 p., 8 figures and references. 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. This work was supported by Deutsche Forschungsgemeinschaft grants (BE 1967/2-1) to W.B. and (SFB-870) J.G., by a grant in aid from the Medical Research Council (U117570528) to F.G., by grants from the Spanish Ministry of Science and Innovation, the Generalitat Valenciana and the Fundación Inocente Inocente to F.J.T., and by a join grant from the Fondation Jerôme Lejeune to W.B. and F.J.T. B.H. was recipient of two Travel-Fellowships of the Generalitat Valenciana. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|