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Neurogenesis refers to the proliferation of neural stem cells or neural progenitor cells undergoing balanced and unbalanced division, gradually differentiated and matured into neurons, and gradually migrated to functional areas, and finally established synaptic connections with other neurons to produce neural functions the process of.
Neurogenesis still exists in the adult mammalian brain, which is called adult neurogenesis.
Adult neurogenesis specifically occurs in two areas, namely the subventricular zone and the granular layer of the hippocampal dentate gyrus.
Adult neural stem cells/progenitor cells (aNSPC) are specifically distributed in these two areas and continue to produce new neurons.
Newborn neurons will further mature, migrate, join neural circuits, and play an important role in neuronal activity, learning and memory, and emotional regulation.
The research on the regulatory mechanism of aNSPC will provide important information for understanding the development and function of the nervous system, and the occurrence/development of neurological diseases.
However, the current understanding of the important scientific problem of how the steady state of aNSPC is regulated is still very limited.
O-linked N-acetylglucosamine modification (O-GlcNAc) is an important post-translational glycosylation modification of protein.
O-GlcNAc modifies the serine or threonine residues of the protein under the catalysis of the glycosyltransferase Ogt; at the same time, it is removed under the catalysis of the glycosidase Oga.
This modification is a dynamic, inducible, and controllable modification method, which is very similar to the phosphorylation of proteins.
Previous studies have shown that O-GlcNAc modification plays an important role in key processes such as transcriptional regulation, cell cycle, metabolic homeostasis, and signal transduction.
In the nervous system, O-GlcNAc has a very high abundance and plays a key function in maintaining the function of nerve cells.
However, most of the current researches on O-GlcNAc modification in nervous system development and diseases are based on neurons, and there are very few studies on neural stem cells.
Recently, the joint team of Professor Li Xuekun, Professor Yi Wen and Professor Shu Qiang of Zhejiang University published a research paper entitled Ogt controls neural stem/progenitor cell pool and adult neurogenesis through modulating Notch signaling in Cell Reports, reporting on Ogt-mediated The O-GlcNAc modification of O-GlcNAc plays an important role in maintaining the adult neural stem cell pool and regulating adult neurogenesis, and reveals the molecular mechanism of O-GlcNAc through dialogue with ubiquitination modification to regulate the Notch1 signaling pathway.
This study first found that Ogt and O-GlcNAc are widely distributed in the hippocampus of adult mice, can be detected in aNSPC, neurons and astrocytes, and are enriched in mature neurons.
Ogt and O-GlcNAc change dynamically, and their content decreases during the differentiation of aNSPC into neurons and glial cells, and rises during the maturation of neurons and astrocytes.
After the aNSPC cultured in vitro lacks Ogt, the modification level of O-GlcNAc decreases, the cell proliferation ability decreases, and the cells tend to differentiate into neurons.
Through the study of aNSPC-specific knockout Ogt mouse model, it is found that Ogt deletion in a short period of time leads to excessive activation of aNSPC, which increases the proportion and number of intermediate progenitor cells produced by aNSPC division, thus increasing the number of new neurons.
However, the excessive activation caused by the long-term lack of Ogt impairs the maintenance of the neural stem cell pool, significantly reduces the number of aNSPC, and the overall adult neurogenesis level declines.
In addition, behavioral experiments show that the lack of Ogt leads to impaired learning and memory abilities in mice.
The Notch signaling pathway is essential for maintaining cell stemness, and the phenotype of aNSPC is very similar when Ogt is absent and Notch signaling is inhibited.
Further RNA sequencing showed that when Ogt was lacking, the transcription level of each target molecule of Notch signal in aNSPC changed; immunoprecipitation experiment (IP) and protein mass spectrometry identification showed that Ogt directly binds to the transmembrane/intracellular segment of Notch1 (TM/ICD).
Catalyzed the O-GlcNAc modification on TM/ICD.
O-GlcNAc on Notch1 exists in its 2264 and 2271 positions.
The O-GlcNAc modification inhibits the binding of Notch1 to the ubiquitin E3 ligase Itch, reduces its ubiquitination modification, and enhances the stability of Notch1 protein, thereby maintaining the Notch signal.
normal level.
Knockdown of Itch in aNSPC can partially rescue the phenotype caused by the deletion of Ogt.
In summary, this work clarifies that Ogt-mediated O-GlcNAc modification regulates the Notch signaling pathway by antagonizing Itch-mediated Notch1 ubiquitination, thereby maintaining the important mechanism of mouse adult neural stem cell homeostasis and adult neurogenesis.
.
The results of this study enrich the understanding of the process of neurodevelopmental regulation, and at the same time provide new strategies for the research on the occurrence and development of neurological diseases.
Chen Junchen, a doctoral student at the Children's Hospital of Zhejiang University School of Medicine/Zhejiang University School of Translational Medicine, is the first author of the paper.
Professor Li Xuekun and Professor Shu Qiang from the Children's Hospital of Zhejiang University School of Medicine, and Professor Yi Wen from the School of Life Sciences of Zhejiang University are the corresponding authors of the paper.
Original link: Platemaker: Instructions for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article, personal forwarding is welcome Sharing, reprinting without permission is prohibited, the author has all legal rights, offenders must be investigated.
Neurogenesis still exists in the adult mammalian brain, which is called adult neurogenesis.
Adult neurogenesis specifically occurs in two areas, namely the subventricular zone and the granular layer of the hippocampal dentate gyrus.
Adult neural stem cells/progenitor cells (aNSPC) are specifically distributed in these two areas and continue to produce new neurons.
Newborn neurons will further mature, migrate, join neural circuits, and play an important role in neuronal activity, learning and memory, and emotional regulation.
The research on the regulatory mechanism of aNSPC will provide important information for understanding the development and function of the nervous system, and the occurrence/development of neurological diseases.
However, the current understanding of the important scientific problem of how the steady state of aNSPC is regulated is still very limited.
O-linked N-acetylglucosamine modification (O-GlcNAc) is an important post-translational glycosylation modification of protein.
O-GlcNAc modifies the serine or threonine residues of the protein under the catalysis of the glycosyltransferase Ogt; at the same time, it is removed under the catalysis of the glycosidase Oga.
This modification is a dynamic, inducible, and controllable modification method, which is very similar to the phosphorylation of proteins.
Previous studies have shown that O-GlcNAc modification plays an important role in key processes such as transcriptional regulation, cell cycle, metabolic homeostasis, and signal transduction.
In the nervous system, O-GlcNAc has a very high abundance and plays a key function in maintaining the function of nerve cells.
However, most of the current researches on O-GlcNAc modification in nervous system development and diseases are based on neurons, and there are very few studies on neural stem cells.
Recently, the joint team of Professor Li Xuekun, Professor Yi Wen and Professor Shu Qiang of Zhejiang University published a research paper entitled Ogt controls neural stem/progenitor cell pool and adult neurogenesis through modulating Notch signaling in Cell Reports, reporting on Ogt-mediated The O-GlcNAc modification of O-GlcNAc plays an important role in maintaining the adult neural stem cell pool and regulating adult neurogenesis, and reveals the molecular mechanism of O-GlcNAc through dialogue with ubiquitination modification to regulate the Notch1 signaling pathway.
This study first found that Ogt and O-GlcNAc are widely distributed in the hippocampus of adult mice, can be detected in aNSPC, neurons and astrocytes, and are enriched in mature neurons.
Ogt and O-GlcNAc change dynamically, and their content decreases during the differentiation of aNSPC into neurons and glial cells, and rises during the maturation of neurons and astrocytes.
After the aNSPC cultured in vitro lacks Ogt, the modification level of O-GlcNAc decreases, the cell proliferation ability decreases, and the cells tend to differentiate into neurons.
Through the study of aNSPC-specific knockout Ogt mouse model, it is found that Ogt deletion in a short period of time leads to excessive activation of aNSPC, which increases the proportion and number of intermediate progenitor cells produced by aNSPC division, thus increasing the number of new neurons.
However, the excessive activation caused by the long-term lack of Ogt impairs the maintenance of the neural stem cell pool, significantly reduces the number of aNSPC, and the overall adult neurogenesis level declines.
In addition, behavioral experiments show that the lack of Ogt leads to impaired learning and memory abilities in mice.
The Notch signaling pathway is essential for maintaining cell stemness, and the phenotype of aNSPC is very similar when Ogt is absent and Notch signaling is inhibited.
Further RNA sequencing showed that when Ogt was lacking, the transcription level of each target molecule of Notch signal in aNSPC changed; immunoprecipitation experiment (IP) and protein mass spectrometry identification showed that Ogt directly binds to the transmembrane/intracellular segment of Notch1 (TM/ICD).
Catalyzed the O-GlcNAc modification on TM/ICD.
O-GlcNAc on Notch1 exists in its 2264 and 2271 positions.
The O-GlcNAc modification inhibits the binding of Notch1 to the ubiquitin E3 ligase Itch, reduces its ubiquitination modification, and enhances the stability of Notch1 protein, thereby maintaining the Notch signal.
normal level.
Knockdown of Itch in aNSPC can partially rescue the phenotype caused by the deletion of Ogt.
In summary, this work clarifies that Ogt-mediated O-GlcNAc modification regulates the Notch signaling pathway by antagonizing Itch-mediated Notch1 ubiquitination, thereby maintaining the important mechanism of mouse adult neural stem cell homeostasis and adult neurogenesis.
.
The results of this study enrich the understanding of the process of neurodevelopmental regulation, and at the same time provide new strategies for the research on the occurrence and development of neurological diseases.
Chen Junchen, a doctoral student at the Children's Hospital of Zhejiang University School of Medicine/Zhejiang University School of Translational Medicine, is the first author of the paper.
Professor Li Xuekun and Professor Shu Qiang from the Children's Hospital of Zhejiang University School of Medicine, and Professor Yi Wen from the School of Life Sciences of Zhejiang University are the corresponding authors of the paper.
Original link: Platemaker: Instructions for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article, personal forwarding is welcome Sharing, reprinting without permission is prohibited, the author has all legal rights, offenders must be investigated.
