embryonic lethality
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Author(s):  
Ram Wagle ◽  
Young-Han Song

Abstract Background Cranial radiation therapy for treating childhood malignancies in the central nervous system or accidental radiation exposure may result in neurological side effects in surviving adults. As tissue homeostasis is maintained by stem cells, understanding the effect of radiation on neural stem cells will provide clues for managing the neurological effects. Drosophila embryos were used as a model system whose sensitivity to irradiation-induced cell death changes from the sensitive to resistant stage during development. Objective Drosophila embryos at the radiation-sensitive stage were irradiated at various doses and the radiation sensitivity was tested regarding the appearance of apoptotic cells in the embryos and the embryonic lethality. Cell fates of the neural stem cells called neuroblasts (NBs) and adult motor function after irradiation were also investigated. Result Irradiation of Drosophila embryos at the radiation-sensitive stage resulted in a dose-dependent increase in the number of embryos containing apoptotic cells 75 min after treatment starting at 3 Gy. Embryonic lethality assayed by hatch rate was induced by 1 Gy irradiation, which did not induce cell death. Notably, no apoptosis was detected in NBs up to 2 h after irradiation at doses as high as 40 Gy. At 3 h after irradiation, as low as 3 Gy, the number of NBs marked by Dpn and Klu was decreased by an unidentified mechanism regardless of the cell death status of the embryo. Furthermore, embryonic irradiation at 3 Gy, but not 1 Gy, resulted in locomotor defects in surviving adults. Conclusion Embryonic NBs survived irradiation at doses as high as 40 Gy, while cells in other parts of the embryos underwent apoptosis at doses higher than 3 Gy within 2 h after treatment. Three hours after exposure to a minimum dose of 3 Gy, the number of NBs marked by Dpn and Klu decreased, and the surviving adults exhibited defects in locomotor ability.


2022 ◽  
Author(s):  
Yan Qin ◽  
Peiling Ni ◽  
Qingye Zhang ◽  
Xiao Wang ◽  
Xiaoling Du ◽  
...  

Hbxip, also named Lamtor5, has been well characterized as a transcriptional coactivator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5. Using Hbxip knockout embryonic stem cells (ESCs), we showed that depletion of Hbxip compromises the self-renewal of ESCs, with reduced expression of pluripotency genes, reduced cell proliferation, and decreased colony forming capacity. In addition, Hbxip-/- ESCs are defective in differentiation, particularly ectodermal and mesodermal differentiation. Consistently, Hbxip-/- epiblast fails to differentiate properly, indicated by sustained expression of Oct4 in E8.5 Hbxip-/- epiblast. Mechanistically, in ESCs, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, display differentiation defects similar to those of Hbxip-/- ESCs. Moreover, Hbxip-/-, p14-/-, and p18-/- mice, lacking subunits of the Ragulator complex, also share similar phenotypes, embryonic lethality and retarded growth around E7-8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.


2022 ◽  
pp. 101574
Author(s):  
Steven Timmermans ◽  
Nicolette J.D. Verhoog ◽  
Kelly Van Looveren ◽  
Sylviane Dewaele ◽  
Tino Hochepied ◽  
...  

2021 ◽  
Vol 8 ◽  
Author(s):  
Yufei Wu ◽  
Yaqun Zhou ◽  
Jian Huang ◽  
Ke Ma ◽  
Tianyou Yuan ◽  
...  

Sorting nexin 17 (SNX17), a member of sorting nexin (SNX) family, acts as a modulator for endocytic recycling of membrane proteins. Results from our previous study demonstrated the embryonic lethality of homozygous defect of SNX17. In this study, we investigated the role of SNX17 in rat fetal development. Specifically, we analyzed patterns of SNX17 messenger RNA (mRNA) expression in multiple rat tissues and found high expression in the cardiac outflow tract (OFT). This expression was gradually elevated during the cardiac OFT morphogenesis. Homozygous deletion of the SNX17 gene in rats resulted in mid-gestational embryonic lethality, which was accompanied by congenital heart defects, including the double-outlet right ventricle and atrioventricular and ventricular septal defects, whereas heterozygotes exhibited normal fetal development. Moreover, we found normal migration distance and the number of cardiac neural crest cells during the OFT morphogenesis. Although cellular proliferation in the cardiac OFT endocardial cushion was not affected, cellular apoptosis was significantly suppressed. Transcriptomic profiles and quantitative real-time PCR data in the cardiac OFT showed that SNX17 deletion resulted in abnormal expression of genes associated with cardiac development. Overall, these findings suggest that SNX17 plays a crucial role in cardiac development.


Author(s):  
Melissa R. Bentley-Ford ◽  
Reagan S. Andersen ◽  
Mandy J. Croyle ◽  
Courtney J. Haycraft ◽  
Kelsey R. Clearman ◽  
...  

Atxn10 is a gene known for its role in cytokinesis and is associated with spinocerebellar ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes nephronophthisis (NPHP) and Joubert syndrome (JBTS), which are caused by the disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here, we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue-specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt ATXN10 systemically at postnatal stages, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial-to-mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively, this study identifies ATXN10 as an essential protein for survival.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3346-3346
Author(s):  
Minako Mori ◽  
Vera Adema ◽  
Carmelo Gurnari ◽  
Simona Pagliuca ◽  
Laila Terkawi ◽  
...  

Abstract Loss of chr7 (-7) and partial deletions of its long arm (del7q) are observed in 10% of de novo myeloid neoplasms (MNs), 50% of therapy related MDS, up to 60% of post aplastic anemia MNs and occur frequently as evolution of congenital bone marrow failure syndromes (e.g., GATA2 and SAMD9L deficiency, FA). LOH of one or more chr7 genes has been considered the culprit in the pathogenesis of -7/del7q MNs. In addition to the loss of protective alleles, deletion resulting in haploinsufficiency (HI) of tumor suppressor genes (TSGs) in CDRs might be also a cause of leukemogenic drive behind -7/del7q. To date, albeit many candidate genes have been associated with -7/del7q, the search for genes responsible for clinical phenotype has failed to identify causative -7/del7q TSGs and their putative loss would be difficult to target. Irrespective of the important goal of clarification of leukemogenic effects of -7/del7q, loss of genes in CDRs may create a vulnerability phenotype, which could be exploited with synthetic lethal approaches. Such strategies would rely on the higher resistance of diploid vs -7/del7q cells, thus allowing for a therapeutic window. Here, we studied the molecular profile of 8160 MN patients (del7q: 1.7%; -7: 6%). EZH2 mutations were enriched in -7/del7q compared to chr7 diploid cases (3.8 vs 1.2%, P<.0001) also by absolute numbers heterozygous mutations were more numerous. We also detected somatic CUX1 mutations (1.7 vs 0.9%), SAMD9/SAMD9L (0.3 vs 0.1%), and LUC7L2 (0.3 vs 0.1%) in -7/del7q vs diploid. In -7/del7 cases somatic alterations were detected in BRAF (n=7), POT1 (n=3), PCLO (n=5) and PSMC2 (n=1) while no mutations in CUL1 and KMT2C were found. We then investigated the presence of driver mutations located on other chromosomes in -7/del7q. Del7q/-7 cases showed a lower frequency of TET2 and SF3B1 mutations vs diploid cases. In isolated/+1 del7q/-7 cases, TP53 mutations were significantly less frequent, but were increased in -7/del7q with complex karyotype (P<.0001). Higher frequencies of RAS genes, RUNX1 and ETV6 hits were also found. Del7q and TP53 mutations were founder lesions (dominant) in 38% and 54% of -7/del7q, while -7 was dominant in 63% of -7 cases. TP53 was the only mutation significantly associated with further worsening the already poor prognosis of -7/del7q cases (HR=1.629 P< .01). Germline alterations were more common in -7/del7q as compared to diploid cases (13 vs 5% P< .0001) of which most were FA or DNA repair gene variants also in other genes including (e.g., SAMD9L, 7%, DDX41, 3.7%). Having defined the genotype of -7/del7q, we set to identify genes which could be possible targets for the therapy chiefly synthetic lethality. Criteria for selection included: consistent HI in most of the patients, genes not affected by hemizygous LOF mutations and embryonic lethality in knockout (KO) configuration. Expression data of -7/del7q (n=86), diploid cases (n=1066) and healthy controls (n=84; MLL and BEAT AML to increase precision) were analyzed. Our algorithm included selection of genes with mRNA expression inversely correlating with copy number (deletion copy number). Out of 694 genes on chr7, 147 genes were deleted in all patients and 101 genes had more inconsistent HI levels. In total 35 genes showed significant negative correlation with -7/del7q ploidyincluding ACTR3B,AGK,ATP06V0E2,CUL1,FASTK,GALNT11,GSTK1, IMPDH1, PLXNA4, SLC37A3, ZNF277, KMT2C, NUP205, TMEM209, ZC3HC1 and GIMAP1/2/4/6, a cluster ofnucleotide binding proteins. Following adjustment to ploidy, HI was found for EZH2 (76% cases), CUX1 (76%), KMT2C (70%), LUC7L2 (60%), and SAMD9/9L (32%/50%) but also even more consistently in SSBP1 (88%), PSMC2 (86%), CUL1, ZNF398, and RHEB (all 84%) and TNPO3 (82%). Among those genes homozygous KO of Ezh2 and Cul1 lead to embryonic lethality, Gimap family deletion reduces normal hematopoiesis, Samd9l +/-and Samd9l-/- mice develop MDS and die after 1.5yrs and Cux1 knockdown causes an MDS like phenotype. Existing inhibitors are available for CUL1 (MLN4924), CUX1 (BER modulating agents) and EZH2 (EPZ6438, GSK343), but the presence of homozygous mutations (UPD7q) argues that EZH2 inhibition is unlikely to be successful. In conclusion, we showed a comprehensive molecular topography of -7/del7q and identified novel HI genes which could be targeted by novel or repurposed drugs. Ongoing drug screens for identified targets performed in cells with -7/del7q will be presented at the meeting. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; Alexion: Consultancy.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elizabeth J. Adams ◽  
Rami Khoriaty ◽  
Anna Kiseleva ◽  
Audrey C. A. Cleuren ◽  
Kärt Tomberg ◽  
...  

AbstractThe COPII component SEC24 mediates the recruitment of transmembrane cargos or cargo adaptors into newly forming COPII vesicles on the ER membrane. Mammalian genomes encode four Sec24 paralogs (Sec24a-d), with two subfamilies based on sequence homology (SEC24A/B and C/D), though little is known about their comparative functions and cargo-specificities. Complete deficiency for Sec24d results in very early embryonic lethality in mice (before the 8 cell stage), with later embryonic lethality (E7.5) observed in Sec24c null mice. To test the potential overlap in function between SEC24C/D, we employed dual recombinase mediated cassette exchange to generate a Sec24cc-d allele, in which the C-terminal 90% of SEC24C has been replaced by SEC24D coding sequence. In contrast to the embryonic lethality at E7.5 of SEC24C-deficiency, Sec24cc-d/c-d pups survive to term, though dying shortly after birth. Sec24cc-d/c-d pups are smaller in size, but exhibit no other obvious developmental abnormality by pathologic evaluation. These results suggest that tissue-specific and/or stage-specific expression of the Sec24c/d genes rather than differences in cargo export function explain the early embryonic requirements for SEC24C and SEC24D.


2021 ◽  
Author(s):  
Simona Abbatemarco ◽  
Alexandra Bondaz ◽  
Francoise Schwager ◽  
Jing Wang ◽  
Christopher M. Hammell ◽  
...  

When exposed to stressful conditions, eukaryotic cells respond by inducing the formation of cytoplasmic ribonucleoprotein complexes called stress granules. Here we use C. elegans to study two proteins that are important for stress granule assembly in human cells: PQN-59, the human UBAP2L ortholog, and GTBP-1, the human G3BP1/2 ortholog. Both proteins assemble into stress granules in the embryo and in the germline when C. elegans is exposed to stressful conditions. None of the two proteins is essential for the assembly of stress-induced granules, as shown by the single and combined depletions by RNAi, and neither pqn-59 nor gtbp-1 mutant embryos show higher sensitivity to stress than control embryos. We find that pqn-59 mutants display reduced progeny and a high percentage of embryonic lethality, phenotypes that are not dependent on stress exposure and that are not shared with gtbp-1 mutants. Our data indicate that, in contrast to human cells, PQN-59 and GTBP-1 are not required for stress granule formation but that PQN-59 is important for C. elegans development.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Benoit Roch ◽  
Vincent Abramowski ◽  
Olivier Etienne ◽  
Stefania Musilli ◽  
Pierre David ◽  
...  

We developed a Xrcc4M61R separation of function mouse line to overcome the embryonic lethality of Xrcc4 deficient mice. XRCC4M61R protein does not interact with Xlf, thus obliterating XRCC4-Xlf filament formation while preserving the ability to stabilize DNA Ligase IV. X4M61R mice, which are DNA repair deficient, phenocopy the Nhej1-/- (known as Xlf -/-) setting with a minor impact on the development of the adaptive immune system. The core NHEJ DNA repair factor XRCC4 is therefore not mandatory for V(D)J recombination aside from its role in stabilizing DNA ligase IV. In contrast, Xrcc4M61R mice crossed on Paxx-/-, Nhej1-/-, or Atm-/- backgrounds are severely immunocompromised, owing to aborted V(D)J recombination as in Xlf-Paxx and Xlf-Atm double KO settings. Furthermore, massive apoptosis of post-mitotic neurons causes embryonic lethality of Xrcc4M61R -Nhej1-/- double mutants. These in vivo results reveal new functional interplays between XRCC4 and PAXX, ATM and Xlf in mouse development and provide new insights in the understanding of the clinical manifestations of human XRCC4 deficient condition, in particular its absence of immune deficiency.


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