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Stabilization of Dll1 mRNA by Elavl1/HuR in neuroepithelial cells undergoing mitosis.

ABSTRACT: In the vertebrate neuroepithelium, the decision to differentiate is made by neural precursors soon after mitosis, when they are apically located. This process is controlled by lateral inhibitory signals triggered by the Delta/Notch pathway. During mitosis, the capacity of neural precursors to express the neurogenic genes Dll1 and Notch1 is maximal due to mRNA stabilization, but the mechanism controlling this process remains unknown. Here we show that Elav-like (Elavl1)/HuR becomes enriched in the cytoplasm of neuroepithelial cells undergoing mitosis and that this ribonucleoprotein interacts with the 3' untranslated region (UTR) of Dll1 mRNA. This interaction is functionally relevant because RNAi against Elavl1 reduces the stability of Dll1-3'UTR-containing transcripts in mitosis-arrested neuroepithelial cells, and Elavl1 null-mutant heterozygous mice show decreased Dll1 expression in the developing brain in vivo. We also show that RNAi against Elavl1 diminishes the capacity of brain precursors to trigger lateral inhibitory signals to their neighbors, an observation consistent with the increase in the rate of neurogenesis which can be detected in vivo in the developing retina of Elavl1 heterozygous mice. We conclude that Elavl1/HuR facilitates the exposure of vertebrate neuronal precursors to apically located Delta/Notch signals.

SUBMITTER: Garcia-Dominguez DJ

PROVIDER: S-EPMC3078063 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Stabilization of Dll1 mRNA by Elavl1/HuR in neuroepithelial cells undergoing mitosis.

García-Domínguez Daniel J DJ Morello Dominique D Cisneros Elsa E Kontoyiannis Dimitris L DL Frade José M JM

Molecular biology of the cell 20110223 8

In the vertebrate neuroepithelium, the decision to differentiate is made by neural precursors soon after mitosis, when they are apically located. This process is controlled by lateral inhibitory signals triggered by the Delta/Notch pathway. During mitosis, the capacity of neural precursors to express the neurogenic genes Dll1 and Notch1 is maximal due to mRNA stabilization, but the mechanism controlling this process remains unknown. Here we show that Elav-like (Elavl1)/HuR becomes enriched in th ...[more]

PMID: 21346194

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Project description:Atherosclerotic plaques are defined by the accumulation of lipids and immune cells beneath the endothelium of the arterial intima. CD8 T cells are among the most abundant immune cell types in plaque, and conditions linked to their activation correlate with increased levels of cardiovascular disease. As lethal effectors of the immune response, CD8 T cell activation is suppressed at multiple levels. These checkpoints are critical in dampening autoimmune responses, and limiting damage in cardiovascular disease. Endothelial cells are well known for their role in recruiting CD8 T and other hematopoietic cells to low and disturbed flow (LDF) arterial regions that develop plaque, but whether they locally influence CD8 effector functions is unclear. Here, we show that endothelial cells can actively suppress CD8 T cell responses in settings of chronic plaque inflammation, but that this behavior is governed by expression of the RNA-binding protein Embryonic Lethal, Abnormal Vision-Like 1 (Elavl1). In response to immune cell recruitment in plaque, the endothelium dynamically shifts splicing of pre-mRNA and their translation to enhance expression of immune-regulatory proteins including C1q and CD27. This program is immuno-suppressive, and limited by Elavl1. We show this by Cdh5(PAC)-CreERT2-mediated deletion of Elavl1 (ECKO), and analysis of changes in translation by Translating Ribosome Affinity Purification (TRAP). In ECKO mice, the translational shift in chronic inflammation is enhanced, leading to increased ribosomal association of C1q components and other critical regulators of immune response and resulting in a ~70% reduction in plaque CD8 T cells. CITE-seq analysis of the remaining plaque T cells shows that they exhibit lower levels of markers associated with T cell receptor (TCR) signaling, survival, and activation. To understand whether the immunosuppressive mechanism occurred through failed CD8 recruitment or local modulation of T cell responses, we used a novel in vitro co-culture system to show that ECKO endothelial cells suppress CD8 T cell expansion-even in the presence of wild-type myeloid antigen-presenting cells, antigen-specific CD8 T cells, and antigen. Despite the induction of C1q mRNA by T cell co-culture in both wild-type and ECKO endothelial cells, we find C1q protein abundantly expressed only in co-culture with ECKO cells. Together, our data define a novel immune-suppressive transition in the endothelium, reminiscent of the transition of T cells to T-regs, and demonstrate the regulation of this process by Elavl1.

Dataset Information

Stabilization of Dll1 mRNA by Elavl1/HuR in neuroepithelial cells undergoing mitosis.

Publications

Stabilization of Dll1 mRNA by Elavl1/HuR in neuroepithelial cells undergoing mitosis.

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