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

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 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.

SUBMITTER: Hammerle B

PROVIDER: S-EPMC3100710 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Hämmerle Barbara B Ulin Edgar E Guimera Jordi J Becker Walter W Guillemot François F Tejedor Francisco J FJ

Development (Cambridge, England) 20110601 12

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 an ...[more]

PMID: 21610031

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Project description:The tailbud is a population of stem cells in the posterior embryonic tail. During zebrafish development, these stem cells give rise to the main structures of the embryo's posterior body, including the tail somites. Progenitor cells reside in the tailbud for variable amounts of time before they exit and begin to differentiate. There must be a careful balance between cells that leave the tailbud and cells that are held back in order to give rise to later somites. However, this meticulous process is not well understood. A gene that has shed some light on this area is the t-box transcription factor spadetail (spt). When spt is mutated, embryos develop an enlarged tailbud and are only able to form roughly half of their somites. This phenotype is due to the fact that some of the somitic precursors are not able to leave the tailbud or differentiate. Another factor involved in tail morphogenesis is the Bone Morphogenetic Protein (BMP) pathway. BMPs are important for many processes during early development, including cell migration. Chordino (chd) is a secreted protein that inhibits BMP signaling. BMPs are upregulated in chd mutants, however, these mutants are able to form organized somites. In embryos where chd and spt are mutated, somites are completely absent. These double mutants also develop a large tailbud due to the accumulation of progenitor cells that are never able to leave or differentiate. To study the dynamics of cells in the tailbud and their role in somite formation, we have analyzed the genetic factors and pathway interactions involved, conducted transplant experiments to look at behavior of mutant cells in different genetic backgrounds, and used time lapse microscopy to characterize cell movements and behavior in wild type and mutant tailbuds. These data suggest that spt expression and BMP inhibition are both required for somitic precursors to exit the tailbud. They also elucidate that chd;spt tailbud mesodermal progenitor cells (MPC) behave autonomously and their dynamics within the tailbud are drastically different than WT MPCs.

Project description:RATIONALE:Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes. OBJECTIVE:To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility. METHODS AND RESULTS:To model an injury response and determine the effects of Notch signaling on atrial electrophysiology, we transiently activate Notch signaling within adult myocardium using a doxycycline-inducible genetic system (inducible Notch intracellular domain [iNICD]). Significant heart rate slowing and frequent sinus pauses are observed in iNICD mice when compared with controls. iNICD mice have structurally normal atria and preserved sinus node architecture, but expression of key transcriptional regulators of sinus node and atrial conduction, including Nkx2-5 (NK2 homeobox 5), Tbx3, and Tbx5 are dysregulated. To determine whether the induced electrical changes are stable, we transiently activated Notch followed by a prolonged washout period and observed that, in addition to decreased heart rate, atrial conduction velocity is persistently slower than control. Consistent with conduction slowing, genes encoding molecular determinants of atrial conduction velocity, including Scn5a (Nav1.5) and Gja5 (connexin 40), are persistently downregulated long after a transient Notch pulse. Consistent with the reduction in Scn5a transcript, Notch induces global changes in the atrial action potential, including a reduced dVm/dtmax. In addition, programmed electrical stimulation near the murine pulmonary vein demonstrates increased susceptibility to atrial arrhythmias in mice where Notch has been transiently activated. Taken together, these results suggest that transient Notch activation persistently alters ion channel gene expression and atrial electrophysiology and predisposes to an arrhythmogenic substrate. CONCLUSIONS:Our data provide evidence that Notch signaling regulates transcription factor and ion channel gene expression within adult atrial myocardium. Notch reactivation induces electrical changes, resulting in sinus bradycardia, sinus pauses, and a susceptibility to atrial arrhythmias, which contribute to a phenotype resembling sick sinus syndrome.

Dataset Information

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

Publications

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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