ZEB1 Links p63 and p73 in a Novel Neuronal Survival Pathway Rapidly Induced in Response to Cortical Ischemia

Background: Acute hypoxic/ischemic insults to the forebrain, often resulting in significant cellular loss of the cortical parenchyma, are a major cause of debilitating injury in the industrialized world. A clearer understanding of the pro-death/ pro-survival signaling pathways and their downstream targets is critical to the development of therapeutic interventions to mitigate permanent neurological damage. Methodology/Principal Findings: We demonstrate here that the transcriptional repressor ZEB1, thought to be involved in regulating the timing and spatial boundaries of basic-Helix-Loop-Helix transactivator-mediated neurogenic determination/ differentiation programs, functions to link a pro-survival transcriptional cascade rapidly induced in cortical neurons in response to experimentally induced ischemia. Employing histological, tissue culture, and molecular biological read-outs, we show that this novel pro-survival response, initiated through the rapid induction of p63, is mediated ultimately by the transcriptional repression of a pro-apoptotic isoform of p73 by ZEB1. We show further that this phylogenetically conserved pathway is induced as well in the human cortex subjected to episodes of clinically relevant stroke. Conclusions/Significance: The data presented here provide the first evidence that ZEB1 induction is part of a protective response by neurons to ischemia. The stroke-induced increase in ZEB1 mRNA and protein levels in cortical neurons is both developmentally and phylogenetically conserved and may therefore be part of a fundamental cellular response to thi

δ-EF1 is a negative regulator of Ihh in the developing growth plate

Hedgehog protein IHH expression is regulated by transcription factor δ-EF1 to control endochondral bone formatio

The Arts: The Voice of the People

The University Committee for Diversity, Equity and Inclusion, in partnership with President Christopher Callahan, presents this series of dialogues designed to offer students an enriched co-curricular experience via participating in dialogues with influential citizen leaders from across the country. The dialogues address the social, cultural and structural inequities in our society and help educate, engage and empower individuals to become transformative leaders in the fight for social justice

The Arts: The Voice of the People

The University Committee for Diversity, Equity and Inclusion, in partnership with President Christopher Callahan, presents this series of dialogues designed to offer students an enriched co-curricular experience via participating in dialogues with influential citizen leaders from across the country. The dialogues address the social, cultural and structural inequities in our society and help educate, engage and empower individuals to become transformative leaders in the fight for social justice

XSIP1, a Xenopus zinc finger/homeodomain encoding gene highly expressed during early neural development.

We have isolated a Xenopus homologue of the zinc finger/homeodomain-containing transcriptional repressor Smad-interacting protein-1 (SIP1) from mouse. XSIP1 is activated at the early gastrula stage and transcription occurs throughout embryogenesis. At the beginning of gastrulation, XSIP1 is strongly expressed in prospective neurectoderm. At the neurula stage, XSIP1 is highly expressed within the neural plate but weakly in the dorsal midline. At later stages of development transcripts are detected primarily within the neural tube and neural crest. In the adult, XSIP1 expression is detected at variable levels in several organs.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe