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

Abstract

SUMMARYThe 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 p27KIP1 expression and suppressing NOTCH signaling.

Harmine stimulates neurogenesis of human neural cells in vitro

“…These results are consistent with the findings published by Hämmerle and others 21 , where harmine exposure to chick embryos resulted in a strong increase in BrdU incorporation and number of mitotic cells in the spinal cord.…”

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

“…18,19,21,44,45 The reduced brain size may be partially explained by the dual role of DYRK1A in inhibiting the proliferation of neuronal progenitors via suppression of NOTCH signaling and Cyclin D1 while also promoting neurogenesis by stabilizing the cyclindependent kinase inhibitor p27 (KIP1) . 46,47 In addition, DYRK1A interacts with the microtubule and actin cytoskeletal networks to regulate neurite outgrowth and synaptogenesis. [48][49][50] Through these mechanisms, haploinsuffciency of DYRK1A presumably leads to augmented neuronal precursor proliferation and apoptosis, decreased neurogenesis and abnormal neuritogenesis.…”

Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control

“…53 It appears likely that more examples for a role of DYRKs as regulators of protein turnover will emerge, both in the regulation of the cell cycle and other cellular processes. Important tasks for the future include the elucidation not only of the exact mechanism of the interaction between DYRKs and the relevant…”