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P53 drives premature neuronal differentiation in response to acute DNA damage during early neurogenesis

ABSTRACT: Purpose: The transcription factor p53 classically regulates the cellular response to DNA damage. Inappropriate activation of p53 during embryonic development can lead to a range of developmental defects such as microcephaly. Here, we studied the cellular and molecular mechanisms underlying microcephaly induced by acute irradiation of mouse fetuses at the onset of neurogenesis. This leads to transient DNA damage followed by apoptosis and premature neuronal differentiation, both of which are p53-dependent as they are reduced in dorsal forebrain-specific Trp53 knockout mice. A functional genomics screen shows that radiation induces the p53-dependent activation of both apoptosis- and differentiation-associated genes. Irradiation furthermore induces an epithelial-to-mesenchymal transition-like process characterized by a reduction of epithelial markers and a disruption of the apical adherens junction belt. Altogether, we have identified a novel function of p53 as an activator of neuronal differentiation in response to acute embryonic DNA damage further demonstrating its importance as a regulator of cell fate. Methods: Pregnant mouse dams were (sham-)irradiated at gestational day 11 after which they were sacrificed for dissection of fetuses after 2 h, 6 h and 12 h. Cerebral cortices were removed for transcriptomic analysis via RNA-seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE140464 | GEO | 2023/03/31

REPOSITORIES: GEO

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Project description:This is the model described the article: GSK3 and p53 - is there a link in Alzheimer's disease? Carole J Proctor and Douglas A Gray Molecular Neurodegeneration 2010, 5:7; doi: 10.1186/1750-1326-5-7 Abstract: Background: Recent evidence suggests that glycogen synthase kinase-3beta (GSK3beta) is implicated in both sporadic and familial forms of Alzheimer's disease. The transcription factor, p53 also plays a role and has been linked to an increase in tau hyperphosphorylation although the effect is indirect. There is also evidence that GSK3beta and p53 interact and that the activity of both proteins is increased as a result of this interaction. Under normal cellular conditions, p53 is kept at low levels by Mdm2 but when cells are stressed, p53 is stabilised and may then interact with GSK3beta. We propose that this interaction has an important contribution to cellular outcomes and to test this hypothesis we developed a stochastic simulation model. Results: The model predicts that high levels of DNA damage leads to increased activity of p53 and GSK3beta and low levels of aggregation but if DNA damage is repaired, the aggregates are eventually cleared. The model also shows that over long periods of time, aggregates may start to form due to stochastic events leading to increased levels of ROS and damaged DNA. This is followed by increased activity of p53 and GSK3beta and a vicious cycle ensues. Conclusions: Since p53 and GSK3beta are both involved in the apoptotic pathway, and GSK3beta overactivity leads to increased levels of plaques and tangles, our model might explain the link between protein aggregation and neuronal loss in neurodegeneration. Notes: The original model submitted by the author had events in it. Since, this model is intended for Stochastic Simulation run and Copasi cannot handle events in Stochastic run, I have replaced the events with piecewise assignment rule. -Viji This model is an extension of Proctor_p53_Mdm2_ATM ( BIOMD0000000188 ). This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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P53 drives premature neuronal differentiation in response to acute DNA damage during early neurogenesis

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