JCI︱Liang Zhang/Zhanxiang Wang's team discovered that autocrine pathway regulates oligodendrocyte differentiation and promotes remyelination

Author︱Liu Zhixiong edits︱Wang SizhenIn the central nervous system, oligodendrocytes are differentiated from oligodendrocyte progenitor cells (OPC), which can form myelin sheaths to wrap nerve axons, thereby The nerve signals are transmitted rapidly along the axon, giving physical protection and energy support to the axon
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In some demyelinating diseases, such as multiple sclerosis, neuromyelitis optica, and leukodystrophy, the loss of myelin impairs nerve signaling, leading to axonal degeneration and neuronal disease [1]
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Therefore, understanding how to promote OPC differentiation has important implications for the treatment of demyelination-related diseases
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 In some neurological diseases, abnormal protein transport and protein aggregation can often be observed [2]
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COPII (coat protein complex II, coat protein complex II) mediates the transport of membrane and soluble proteins from the endoplasmic reticulum to the Golgi apparatus and consists of five core components, including Sar1 and two complexes Sec23-Sec24 and Sec13- Sec31
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Dysfunction of COPII inhibits protein secretion and affects cell differentiation and homeostasis, and many studies have shown a link between COPII components and human diseases [3,4], such as Sec31 mutations leading to severe neurological syndromes [5]
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The surface area of ​​oligodendrocytes becomes more than 6500 times larger during differentiation and needs to undergo very active cargo transport[6]
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However, the physiological functions and underlying mechanisms of COPII components in oligodendrocyte differentiation and myelination are currently unclear
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 Recently, Zhang Liang's team and Wang Zhanxiang's team from Xiamen University published a research paper entitled "Sec13 promotes oligodendrocyte differentiation and myelin repair through autocrine pleiotrophin signaling" in The Journal of Clinical Investigation, revealing that the process of oligodendrocyte differentiation is Physiological functions and mechanisms of action of COPII
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The expression of COPII components is up-regulated during myelination.
Knockout of COPII component Sec13 leads to myelination disorders.
Sec13 mediates the autocrine of PTN, and the secreted PTN can promote oligodendrocyte differentiation and accelerate myelination.
Damage repair
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This article is the first to discover that autocrine plays an important role in oligodendrocyte differentiation and remyelination, which provides a new idea for the treatment of demyelination-related diseases
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In order to understand the role of COPII vesicle transport in the process of myelination, the authors first treated mice with myelin injury with TUDCA, a drug that promotes protein transport, and found that TUDCA can accelerate the speed of myelin repair; inhibiting endoplasmic reticulum to Golgi apparatus Treatment of oligodendrocyte precursor cells (OPCs) with the protein transport drug BFA significantly inhibited their ability to differentiate into myelin sheaths (Figure 1), suggesting that protein transport is involved in oligodendrocyte differentiation and remyelination
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Next, the authors analyzed the expression patterns of COPII components during OPC differentiation and found that the expressions of Sec13 and Sec31A were up-regulated after myelin injury
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At the same time, knockdown of each component of COPII inhibited the expression of myelin genes
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These results suggest that COPII is required for OPC differentiation
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Figure 1 Protein transport is required for myelination (Source: Liu Z, et al.
, J Clin Invest, 2022) The authors of the paper constructed a conditional knockout mouse of Sec13
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It has been confirmed in mice, in vitro and in the repair of myelin damage that Sec13 is required for OPC differentiation to form myelin
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So how does knockdown of Sec13 lead to abnormal myelination? To answer this question, the authors of the paper firstly understood the function of Sec13, which can act as a component of COPII, a nuclear pore complex, and a component of GATOR2 of the mTOR pathway, respectively
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However, the authors did not detect any significant impact on the function of the nuclear pore complex or the mTOR pathway after Sec13 deletion
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At the same time, the authors found that the conditioned medium of differentiated oligodendrocytes can promote OPC differentiation, using liquid-phase mass spectrometry analysis to detect the increase of secreted proteins during OPC differentiation, and the loss of Sec13 leads to the decrease of the secretion of these proteins
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 Pleiotrophin (PTN) is a nerve growth factor involved in a variety of physiological processes, including cell differentiation, proliferation, migration, and angiogenesis
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The authors found that among the secreted proteins regulated by Sec13, PTN could significantly promote OPC differentiation after being secreted, while PTN with a mutated signal peptide could not be secreted to play a promoting role, and the secretion of PTN was dependent on Sec13
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In addition, PTN can compensate for the abnormal OPC differentiation phenotype caused by Sec13 knockdown, indicating that Sec13 regulates myelination mainly through the secretion of PTN (Figure 2)
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So, through what pathway does PTN affect myelination? Using co-immunoprecipitation and western blotting experiments, the authors found that PTN acts on the cell membrane receptor PTPRZ1, causing phosphorylation of P190, thereby promoting myelination
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Finally, through in vivo experiments, it was further verified that PTN can promote the process of remyelination
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Figure 2 PTN promotes oligodendrocyte differentiation through the autocrine pathway (Source: Liu Z, et al.
, J Clin Invest, 2022) Conclusion and discussion, inspiration and prospect In conclusion, this study not only provides Solid evidence demonstrates that components of coat protein complex II (COPII) are involved in oligodendrocyte differentiation in the central nervous system, and provides a new basis for oligodendrocytes to regulate myelin development and regeneration in an autocrine manner, The autocrine factor PTN (pleiotrophin) that promotes myelination and its pathway of action are verified, providing a new clinical drug target for the treatment of demyelinating diseases
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 This study still has limitations
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First, according to mass spectrometry analysis, the secretion of proteins is dynamic before and after oligodendrocyte differentiation, and it would be interesting to further understand the effects of these secreted factors on oligodendrocytes themselves or other cells under different conditions
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Furthermore, since OPCs change in surface area thousands of times during differentiation, the effect of COPII on membrane protein trafficking remains to be explored
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Link to the original text: http:// The first authors of this article are postdoctoral fellow Liu Zhixiong, doctoral student Yan Minbiao and master student Lei Wanying of Xiamen University.
The corresponding authors are Associate Professor Zhang Liang of the School of Life Sciences of Xiamen University and Xiamen University.
Professor Wang Zhanxiang from the First Affiliated Hospital of the University
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The research is funded by the National Natural Science Foundation of China, the Fundamental Research Fund for Central Universities and the National Key R&D Program
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The first author Liu Zhixiong (the third from the left in the back row), the co-first author Yan Minbiao (the second from the left in the back row), the co-first author Lei Wanying (the first from the left in the back row), and the corresponding author Zhang Liang (the third from the right in the back row) (photo provided) From: Zhang Liang/Wang Zhanxiang's team of Xiamen University) Co-corresponding author Prof.
Wang Zhanxiang (Photo provided by: Zhang Liang/Wang Zhanxiang's team of Xiamen University) Selected previous articles [1] Front Cell Neurosci Review︱Microglia membrane proteins or receptors in The role and research progress in neuroinflammation and degeneration【2】Nat Biomed Eng︱Utilizing infrared light through the brain to regulate deep brain nerve activity【3】Review by Neurosci Bull︱ Research progress of humoral biomarkers in Alzheimer's disease , Problems and Prospects【4】Current Biology︱Chen Zhong’s team made new achievements in the mechanism of histamine regulation of feeding: H2 receptor-dependent medial septal histaminergic circuit【5】Nat Commun︱Guo Ming’s team discovered a new mechanism of mitochondrial fission Collaborating with a new target for the prevention and treatment of Parkinson's disease [6] Front Cell Neurosci︱Shi Peng/Liu Zhen's research group revealed the shared molecular mechanism of sensorineural hearing loss caused by multiple factors [7] Cell Death Dis︱Li Xian's research group revealed oligodendrogenesis The role of ferroptosis of glial precursor cells in white matter damage after intracerebral hemorrhage [8] Front Mol Neurosci︱ Gao Shangbang's research group to analyze the composition and molecular mechanism of motor neuron oscillators [9] Review of Nat Neurosci︱ Two-photon holographic optogenetics Science and technology to detect neural coding [10] Mol Psychiatry︱ The role of biological clock gene Bmal1 in mouse models of autism and cerebellar ataxia Recommended for high-quality scientific research training courses [1] Scientific research skills︱ The fourth session of near-infrared brain function data analysis Class (Online: 2022.
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18~4.
30) [2] Scientific Research Skills︱Introduction to Magnetic Resonance Brain Network Analysis (Online: 2022.
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6~4.
16) [3] Training Course︱Scientific Research Drawing and Academic Image Training References ( Swipe up and down) [1] Murta V, Ferrari C.
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Plate making︱Wang Sizhen End of this articleet al.
Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation[J].
Nat Genet, 2006, 38(10): 1198-203.
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The COPII cargo adapter SEC24C is essential for neuronal homeostasis[J].
J Clin Invest, 2018, 128(8): 3319-3332.
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SEC31A mutation affects ER homeostasis, causing a neurological syndrome[J].
J Med Genet, 2019, 56(3): 139-148.
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On the biogenesis of myelin membranes: sorting, trafficking and cell polarity[J].
FEBS Lett, 2010 , 584(9): 1760-70.
Plate making︱Wang Sizhen End of this articleet al.
Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation[J].
Nat Genet, 2006, 38(10): 1198-203.
[4] Wang B, Joo JH, Mount R, et al.
The COPII cargo adapter SEC24C is essential for neuronal homeostasis[J].
J Clin Invest, 2018, 128(8): 3319-3332.
[5] Halperin D, Kadir R, Perez Y, et al.
SEC31A mutation affects ER homeostasis, causing a neurological syndrome[J].
J Med Genet, 2019, 56(3): 139-148.
[6] Baron W, Hoekstra D.
On the biogenesis of myelin membranes: sorting, trafficking and cell polarity[J].
FEBS Lett, 2010 , 584(9): 1760-70.
Plate making︱Wang Sizhen End of this article2018, 128(8): 3319-3332.
[5] Halperin D, Kadir R, Perez Y, et al.
SEC31A mutation affects ER homeostasis, causing a neurological syndrome[J].
J Med Genet, 2019, 56(3) : 139-148.
[6] Baron W, Hoekstra D.
On the biogenesis of myelin membranes: sorting, trafficking and cell polarity[J].
FEBS Lett, 2010, 584(9): 1760-70.
Plate making︱Sizhen Wang End of this paper2018, 128(8): 3319-3332.
[5] Halperin D, Kadir R, Perez Y, et al.
SEC31A mutation affects ER homeostasis, causing a neurological syndrome[J].
J Med Genet, 2019, 56(3) : 139-148.
[6] Baron W, Hoekstra D.
On the biogenesis of myelin membranes: sorting, trafficking and cell polarity[J].
FEBS Lett, 2010, 584(9): 1760-70.
Plate making︱Sizhen Wang End of this paper