Transient expression of Mnb/Dyrk1A couples cell cycle exit and neuronal differentiation of neuronal precursors in the vertebrate CNS by inducing p27 expression and suppressing NOTCH signaling

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 critical step in the generation of cell diversity in the nervous system. Here, we show that the Down’s syndrome candidate Mnb/Dyrk1A gene 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 up regulate 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 in cell cycle exit of vertebrate CNS neurons. All these actions required the MNB/DYRK1A kinase activity. We also observed that MNB/DYRK1A is coexpressed with the NOTCH ligand Delta-1 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 it 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.