scholarly journals Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of ATRIP-Seckel syndrome

2020 ◽  
Vol 13 (10) ◽  
pp. dmm045807 ◽  
Author(s):  
Gabriel E. Matos-Rodrigues ◽  
Pedro B. Tan ◽  
Maurício Rocha-Martins ◽  
Clara F. Charlier ◽  
Anielle L. Gomes ◽  
...  
Keyword(s):  
Stress Response ◽  
Progenitor Cells ◽  
Neuronal Degeneration ◽  
Replication Stress ◽  
Seckel Syndrome ◽  
Loss Of Vision ◽  
Replicative Stress ◽  
Photoreceptor Neurons ◽  
And Function ◽  
Retinal Dysplasia

ABSTRACTSeckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR and ATRIP, are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development and function of the central nervous system (CNS). Here, we investigated the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing murine neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons did not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) led to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we showed that RPCs lacking functional ATRIP exhibited higher levels of replicative stress and accumulated endogenous DNA damage that was accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevented apoptosis of Atrip-deficient progenitor cells and was sufficient to rescue retinal dysplasia, neurodegeneration and loss of vision. Together, these results reveal an essential role of ATRIP-mediated replication stress response in CNS development and suggest that the TRP53-mediated apoptosis of progenitor cells might contribute to retinal malformations in Seckel syndrome and other MPD disorders.This article has an associated First Person interview with the first author of the paper.

scholarly journals Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress

Blood ◽  
2017 ◽  
Vol 129 (18) ◽  
pp. 2479-2492 ◽  
Author(s):  
Wei Shi ◽  
Therese Vu ◽  
Didier Boucher ◽  
Anna Biernacka ◽  
Jules Nde ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Apoptotic Cell ◽  
Replication Stress ◽  
Cell Loss ◽  
Hematopoietic Stem ◽  
Replicative Stress ◽  
Key Points ◽  
Stem And Progenitor Cells ◽  
Cell Cycling

Key Points Combined loss of Ssb1/Ssb2 induces rapid lethality due to replication stress–associated loss of hematopoietic stem and progenitor cells. Functionally, loss of Ssb1/Ssb2 activates p53 and IFN pathways, causing enforced cell cycling in quiescent HSPCs and apoptotic cell loss.

scholarly journals DDK/Hsk1 phosphorylates and targets fission yeast histone deacetylase Hst4 for degradation to stabilize stalled DNA replication forks

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shalini Aricthota ◽  
Devyani Haldar
Keyword(s):  
Stress Response ◽  
Fission Yeast ◽  
Cancer Therapeutics ◽  
Replication Stress ◽  
S Phase ◽  
Replication Forks ◽  
Checkpoint Activation ◽  
Fork Protection Complex ◽  
And Function ◽  
Replication Initiator

In eukaryotes, paused replication forks are prone to collapse, which leads to genomic instability, a hallmark of cancer. Dbf4 Dependent Kinase (DDK)/Hsk1Cdc7 is a conserved replication initiator kinase with conflicting roles in replication stress response. Here, we show that fission yeast DDK/Hsk1 phosphorylates sirtuin, Hst4 upon replication stress at C-terminal serine residues. Phosphorylation of Hst4 by DDK marks it for degradation via the ubiquitin ligase SCFpof3. Phosphorylation defective hst4 mutant (4SA-hst4) displays defective recovery from replication stress, faulty fork restart, slow S-phase progression and decreased viability. The highly conserved Fork Protection Complex (FPC) stabilizes stalled replication forks. We found that the recruitment of FPC components, Swi1 and Mcl1 to the chromatin is compromised in the 4SA-hst4 mutant, although whole cell levels increased. These defects are dependent upon H3K56ac and independent of intra S-phase checkpoint activation. Finally, we show conservation of H3K56ac dependent regulation of Timeless, Tipin and And-1 in human cells. We propose that degradation of Hst4 via DDK increases H3K56ac, changing the chromatin state in the vicinity of stalled forks facilitating recruitment and function of FPC. Overall, this study identified a crucial role of DDK and FPC in the regulation of replication stress response with implications in cancer therapeutics.

scholarly journals An Eye in the Replication Stress Response: Lessons From Tissue-Specific Studies in vivo

2021 ◽  
Vol 9 ◽  
Author(s):  
Gabriel E. Matos-Rodrigues ◽  
Rodrigo A. P. Martins
Keyword(s):  
Stress Response ◽  
Progenitor Cells ◽  
Eye Development ◽  
Replication Stress ◽  
Cell Types ◽  
Tissue Specific ◽  
Ocular Manifestations ◽  
Molecular Machinery ◽  
Different Cell Types

Several inherited human syndromes that severely affect organogenesis and other developmental processes are caused by mutations in replication stress response (RSR) genes. Although the molecular machinery of RSR is conserved, disease-causing mutations in RSR-genes may have distinct tissue-specific outcomes, indicating that progenitor cells may differ in their responses to RSR inactivation. Therefore, understanding how different cell types respond to replication stress is crucial to uncover the mechanisms of RSR-related human syndromes. Here, we review the ocular manifestations in RSR-related human syndromes and summarize recent findings investigating the mechanisms of RSR during eye development in vivo. We highlight a remarkable heterogeneity of progenitor cells responses to RSR inactivation and discuss its implications for RSR-related human syndromes.

scholarly journals The Musashi proteins MSI1 and MSI2 are required for photoreceptor morphogenesis and vision in mice

2020 ◽  
pp. jbc.RA120.015714
Author(s):  
Jesse Sundar ◽  
Fatimah Matalkah ◽  
Bohye Jeong ◽  
Peter Stoilov ◽  
Visvanathan Ramamurthy
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neuronal Degeneration ◽  
Critical Role ◽  
Conditional Knockout ◽  
Cell Renewal ◽  
Rod Photoreceptor ◽  
Photoreceptor Outer Segment ◽  
Photoreceptor Neurons ◽  
And Function

The Musashi family of RNA-binding proteins is known for its role in stem-cell renewal and are negative regulators of cell differentiation. Interestingly, in the retina, the Musashi proteins MSI1 and MSI2 are differentially expressed throughout the cycle of retinal development, with MSI2 protein displaying robust expression in the adult retinal tissue. In this study, we investigated the importance of Musashi proteins in the development and function of photoreceptor neurons in the retina. We generated a pan-retinal and rod photoreceptor neuron-specific conditional knockout mouse lacking MSI1 and MSI2. Independent of sex, photoreceptor neurons with simultaneous deletion of Msi1 and Msi2 were unable to respond to light and displayed severely disrupted photoreceptor outer segment morphology and ciliary defects. Mice lacking MSI1 and MSI2 in the retina exhibited neuronal degeneration, with complete loss of photoreceptors within six months. In concordance with our earlier studies that proposed a role for Musashi proteins in regulating alternative splicing, the loss of MSI1 and MSI2 prevented the use of photoreceptor-specific exons in transcripts critical for OS morphogenesis, ciliogenesis and synaptic transmission. Overall, we demonstrate a critical role for Musashi proteins in the morphogenesis of terminally differentiated photoreceptor neurons. This role is in stark contrast with the canonical function of these two proteins in the maintenance and renewal of stem cells.

Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

2014 ◽  
Author(s):  
Shiaw-Yih Lin ◽  
Chun-Jen Lin ◽  
Lili Gong ◽  
Hui Dai ◽  
Ju-Seog Lee
Keyword(s):  
Breast Cancer ◽  
Stress Response ◽  
Replication Stress

scholarly journals Low Replicative Stress Triggers Cell-Type Specific Inheritable Advanced Replication Timing

2021 ◽  
Vol 22 (9) ◽  
pp. 4959
Author(s):  
Lilas Courtot ◽  
Elodie Bournique ◽  
Chrystelle Maric ◽  
Laure Guitton-Sert ◽  
Miguel Madrid-Mencía ◽  
...  
Keyword(s):  
Replication Timing ◽  
Replication Stress ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Replicative Stress ◽  
Daughter Cells ◽  
Origin Activation ◽  
Cell Type Specific ◽  
Cellular Identity ◽  
Dna Replication Timing

DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin. We report that RT advances are cell-type-specific and involve large heterochromatin domains. Importantly, we found that some major late to early RT advances can be inherited by the unstressed next-cellular generation, which is a unique process that correlates with enhanced chromatin accessibility, as well as modified replication origin landscape and gene expression in daughter cells. Collectively, this work highlights how low replication stress may impact cellular identity by RT advances events at a subset of chromosomal domains.

Progenitor Cells: Megakaryocyte Development and Function.

Science ◽  
1987 ◽  
Vol 235 (4784) ◽  
pp. 96a-96a
Author(s):  
D. G. NATHAN
Keyword(s):  
Progenitor Cells ◽  
And Function

scholarly journals Quantitative and functional evaluation of endothelial progenitor cells in patients with cardiac amyloidosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
O Itzhaki Ben Zadok ◽  
D Leshem-Lev ◽  
T Ben-Gal ◽  
A Hamdan ◽  
N Schamroth-Pravda ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Mtt Assay ◽  
Cardiac Amyloidosis ◽  
Microvascular Dysfunction ◽  
Functional Evaluation ◽  
Endothelial Progenitor ◽  
Colony Forming Units ◽  
Study Population ◽  
And Function

Abstract Background Endothelial microvascular dysfunction is a known mechanism of injury in cardiac amyloidosis (CA), but evidence regarding the level and function of endothelial progenitor cells (EPCs) in patients with CA is lacking. Methods Study population included patients with light-chain or transthyretin (ATTR) CA. Patients with diagnosed heart failure and preserved ejection fraction (HFpEF) without monoclonal gammopathy and a 99mTc-DPD scan incompatible with TTR were used as controls. Blood circulating EPCs were assessed quantitatively by the expression of VEGFR-2(+), CD34(+) and CD133(+) using flow cytometry, and functionally by the formation of colony forming units (CFUs). MTT assay was used to demonstrate cell viability. Tests were repeated 3 months following the initiation of amyloid-suppressive therapies (either ATTR-stabilizer or targeted chemotherapy) in CA patients. Results Our preliminary cohort included 14 CA patients (median age 74 years, 62% ATTR CA). Patients with CA vs. patients with HFpEF (n=8) demonstrated lower expression of CD34(+)/VEGFR-2(+) cells [0.51% (IQR 0.4, 0.7) vs. 1.03% (IQR 0.6, 1.4), P=0.043] and CD133(+)/VEGFR-2(+) cells [0.35% (IQR 0.23, 0.52) to 1.07% (IQR 0.6, 1.5), P=0.003]. Functionally, no differences were noted between groups. Following the initiation of amyloid-suppressive therapies in CA patients, we observed the up-regulation of CD34(+)/VEGFR-2(+) cells [2.47% (IQR 2.1, 2.7), P<0.001] and CD133(+)/VEGFR-2(+) cells [1.38% (IQR 1.1, 1.7), P=0.003]. Moreover, functionally, active EPCs were evident microscopically by their ability to form colonies (from 0.5 CFUs [IQR 0, 1.5) to 2 CFUs (IQR 1, 3.5), P=0.023]. EPCs' viability was demonstrated by an MTT assay [0.12 (IQR 0.04, 0.12) to 0.24 (IQR 0.16, 0.3), p=0.014]. Conclusions These preliminary results demonstrate reduced EPCs levels in CA patients indicating significant microvascular impairment. Amyloid-targeted therapies induce the activation of EPCs, thus possibly promoting endothelial regeneration. These findings may represent a novel mechanism of action of amyloid-suppressive therapies EPCs in CA patients and during therapy Funding Acknowledgement Type of funding source: None

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