Tag Archives: #necrosis

Continuous Activation of Immune Response Mediated by Gene Ne2 Results in Hybrid Necrosis in Wheat (Agriculture)

Wheat is one of the most important food crops in the world. Hybrid necrosis often occurs in the process of wheat improvement, which seriously hinders the combination of superior traits among different genotypes of wheat. In the 1960s, scientists demonstrated that the hybrid necrosis in wheat was controlled by a pair of complementary genes, Ne1 and Ne2. However, the formation mechanism of hybrid necrosis in wheat has still not been uncovered. 

Recently, the research group led by Prof. LING Hongqing from the Institute of Genetics and Developmental Biology (IGDB) of the Chinese Academy of Sciences performed a series of experiments to isolate the responsible genes and illustrate the formation mechanism of wheat hybrid necrosis. 

The researchers carried out the preliminary map of Ne1 and Ne2 by genome-wide association analysis. Then, they cloned Ne2 by map-based cloning approach using residual heterozygous lines of Ne2 locus (carrying Ne1Ne1Ne2ne2 genotype) from the recombination inbred line population derived from common wheat varieties “Zhengnong 17” (ne1ne1Ne2Ne2) and “Yangbaimai” (Ne1Ne1ne2ne2). Ne2 encodes a coiled coil-nucleotide-binding site-leucine-rich repeat (CC-NBS-LRR) domain protein. 

Furthermore, they demonstrated that Ne2 was the gene responded for wheat hybrid necrosis via knocking out of Ne2. Homozygous frameshift mutations of Ne2 generated by CRISPR/Cas9 in the genetic background of necrotic lines NIL-Ne2 and RIL-66 resulted in normal leaf growth.

Frameshift mutations of Ne2 generated by CRISPR/Cas9 in the genetic background of necrotic lines NIL-Ne2 and RIL-66 restored normal leaf growth (Image IGDB)

qPCR analysis and histological staining revealed that the immune response in the necrotic plants was continuously activated. Therefore, they concluded that up-regulated expression of Ne2 induced by Ne1 and excessive accumulation of hydrogen peroxide (H2O2) were closely related to the formation of hybrid necrosis in wheat. 

Combined with previous reports, they speculated that Ne2 and leaf rust resistance gene LrLC10/Lr13 might be the same gene according to analysis results of genetics, collinearity of the Ne2 candidate interval and sequence alignment. 

Using the developed diagnostic marker for Ne2 allele, they tested 501 common wheat materials (including 301 cultivars, 200 landraces) from different countries of the world and found that the frequency of Ne2 allele in landrace (2.0%) was much lower than that in modern cultivars (13.6%). The result showed that Ne2/LrLC10/Lr13 had been partially used during wheat genetic improvement, and its utilization was limited by the existence of Ne1 gene. 

This work provides an opportunity to further investigate the molecular mechanism of hybrid necrosis, to select Lr13 by molecular marker-assisted selection, and to avoid hybrid necrosis simultaneously. 

This study entitled “Ne2, a typical CC-NBS-LRR-type gene, is responsible for hybrid necrosis in wheat” was published online in New Phytologist on June 23. 

This research was supported by the National Natural Science Foundation of China, the Major Basic Research Program of Shandong Natural Science Foundation, and the Research Program of Hebei Science and Technology.

Reference: Si, Y., Zheng, S., Niu, J., Tian, S., Gu, M., Lu, Q., He, Y., Zhang, J., Shi, X., Li, Y. and Ling, H.-Q. (2021), Ne2, a typical CC-NBS-LRR-type gene, is responsible for hybrid necrosis in wheat. New Phytologist. Accepted Author Manuscript. https://doi.org/10.1111/nph.17575

Provided by Chinese Academy of Sciences

White Blood Cells May Cause Tumor Cell Death — But That’s Not Good News (Medicine)

White blood cells are part of many immune system responses in the human body. New research shows that a specific type of those cells may cause brain cancer tissues to die — but that’s not good news, according to researchers at Penn State College of Medicine. They said that higher amounts of this tissue death have been associated with poor survival in patients with aggressive glioblastomas, a deadly type of brain cancer that is common in adults.

Neutrophils, stained brown, are visible in a human glioblastoma tissue sample, where tumor cells are stained in blue. © Penn State College of Medicine

Wei Li, assistant professor of pediatrics and biochemistry and molecular biology, studied the causes of this tissue death, called necrosis. Scientists have suggested that a lack of oxygen due to poor blood supply from rapid tumor growth may cause necrosis, but Li and a team of researchers investigated the molecular processes that cause this tissue death to occur. Their findings were published in Nature Communications.

“Glioblastoma patients with higher degrees of necrosis have a poor chance of survival,” Li said. “We hope insight into the processes that drive this tissue death can help us develop new therapeutics to improve outcomes for these patients.”

Li and the research team, including medical scientist training program student Patricia Yee, found that ferroptosis, a specific type of regulated cell death, caused tissue death. They examined tumor tissue samples from animal models of glioblastoma under a microscope and found that neutrophils, a type of white blood cell, were present in the same areas as dead tumor cells.

To establish whether these cells were part of the tissue death process, they decreased the amount of neutrophils in animal models, which then decreased the amount of necrosis in those cancer models. They also isolated these white blood cells and tested them against cancer cells in a lab and found that the presence of neutrophils prevented the cancer cells from thriving.

“We confirmed our theory on the role of neutrophils in necrosis by evaluating glioblastoma patient data,” Li said. “A high number of neutrophils and the presence of genetic signals of ferroptosis were associated with pathological evidence of necrosis and predicted poor survival in patients.”

Although they had a better idea of the key factor driving the tissue death, Li and colleagues were unsure why the tissue death was beneficial to tumor progression. They studied glioblastoma patient data sets and found that the dead cells secrete molecular signals that may help tumor cells grow.

Li, a Penn State Cancer Institute researcher, said future studies will investigate how the white blood cells that spur on the tissue death arrive at the tumor to begin with. He suspects that tissue damage from the tumor growth may be causing the neutrophils to arrive, but that further studies are needed. He also said more research is needed to better understand how necrosis promotes cancer growth.

“If we can develop therapeutic approaches for preventing necrosis, there’s a chance those tumors might be less aggressive, which could be beneficial to glioblastoma patients,” Li said.

Dawit Aregawi, Michael Glantz, Brad Zacharia and Hong-Gang Wang of Penn State Cancer Institute; Krishnamoorthy Thamburaj of Penn State Neuroscience Institute; Stephen Chih of Penn State College of Medicine Medical Scientist Training Program; and Yiju Wei, Soo-Yeon Kim, Tong Lu, Cynthia Lawson, Miaolu Tang, Zhijun Liu, Benjamin Anderson, Megan Young and Charles Specht of Penn State College of Medicine also contributed to this research.

This research was supported by the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

This research was also supported by the Meghan Rose Bradley Foundation, the American Cancer Society, Four Diamonds, and Penn State College of Medicine’s Medical Scientist Training Program.

Reference: Yee, P.P., Wei, Y., Kim, SY. et al. Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression. Nat Commun 11, 5424 (2020). https://www.nature.com/articles/s41467-020-19193-y https://doi.org/10.1038/s41467-020-19193-y

Provided by Penn State