Glia︱Yuan Jianqiang's group reveals a new mechanism for regulating the proliferation of oligodendrocyte precursor cells: c-Abl phosphorylates Olig2

Author ︱ Yuan Zengqiang, Wang Shukun, Zhang Jun editor ︱ Wang Sizhen Myelin provides protection and metabolic nutritional support for axons, ensures the integrity of neurons, realizes the jump conduction of action potentials, and accelerates nerve signal transmission.
It is highly complex.
The basis for the formation of the central nervous system [1]
.

Insufficient myelin formation or blocked regeneration affects the high-level functions of the brain, and eventually causes neurological diseases such as mental and degenerative diseases [2]
.

Therefore, in-depth study of myelination has important theoretical and practical significance for the clinical treatment of neurodevelopmental abnormalities and related diseases
.

 Oligodendrocytes (oligodendrocytes, OLs) are myelin cells in the central nervous system, which are proliferated and differentiated from oligodendrocyte precursor cells (OPCs) [3]
.

Proliferation of OPCs is essential in myelination and remyelination
.

As a member of the basic helix-loop-helix (bHLH) transcription factor family, Olig2 is continuously expressed during OLs development and is a major determinant of OPCs specificity
.

However, little is known about the post-translational modification of Olig2 in the proliferation of OPCs
.

 The non-receptor tyrosine kinase c-Abl is widely expressed in cells and has many downstream substrates, and it plays a variety of important biological functions in vivo [4]
.

In recent years, c-Abl has been widely studied in the central nervous system and is involved in the occurrence and development of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and motor neuron disease
.

However, the biological function of c-Abl during glial cell development remains unclear
.

 On February 13, 2022, Yuan Zeng's research group from the Academy of Military Medicine, Academy of Military Sciences published a research paper entitled "c-Abl-induced Olig2 phosphorylation regulates the proliferation of oligodendrocyte precursor cells" on Glia, revealing that c-Abl mediates Olig2 phosphorylation regulates the proliferation of oligodendrocyte precursor cells
.

Zhang Jun, a graduate student jointly trained by Qingdao University, and Dr.
Sun Jianguang from the Military Medical Research Institute are the co-first authors of the paper, and researcher Yuan Qiangqiang is the corresponding author of the paper
.

The study found that specific knockout of c-Abl resulted in decreased oligodendrocyte lineage gene expression, insufficient OPCs proliferation, and blocked myelin formation; in a bicyclohexanone oxalyl dihydrazone (CPZ)-induced demyelination model, specific Remyelination was delayed in c-Abl knockout mice
.

Mechanistic studies have shown that c-Abl phosphorylates Olig2 at tyrosine 137 and promotes Olig2 homodimerization to maintain OPCs proliferation
.

The study also found that long-term use of the clinical drug nilotinib has potential neurotoxic side effects
.

 Myelinating cells in the brain - oligodendrocytes - are differentiated from oligodendrocyte precursor cells (OPCs), which proliferate during myelination and demyelination during nervous system development.
Remyelination is essential [3]
.

The transcription factor Olig2 is expressed in the oligodendrocyte lineage
.

However, little is known about the post-translational modification of Olig2 in the proliferation of OPCs
.

Receptor tyrosine kinases and their ligands (FGFR1/2) are involved in OPC proliferation and differentiation.
Non-receptor tyrosine kinase c-Abl is localized in the nucleus and cytoplasm, and has been found to be involved in growth factor signal transduction and other process [5]
.

However, the role of c-Abl in OL lineage development has not been reported
.

 The authors first detected the expression of c-Abl in different stages of brain development and in different primary neurons, and found that with the development of the brain, the expression level of c-Abl gradually decreased, was highly expressed in OPC, and co-localized with OPC-specific markers (Fig.
1), suggesting that c-Abl may play an important role in oligodendrocyte development
.

The researchers found abnormal myelin development in c-Abl cKO mice at day 14, with a reduced proportion of myelinated axons, a decrease in the number of PDGFRa/Olig2 double-positive cells (OPC) and CC1Olig2 double-positive cells (OL), and BrdU labeling.
The number of OPC proliferating cells was significantly reduced (Fig.
2), which indicated that c-Abl played an important role in OPC proliferation
.

Meanwhile, the authors verified in vitro that c-Abl phosphorylates Olig2 to promote OPC proliferation
.

Figure 1 Expression patterns of c-Abl in the brain and different nerve cells (Source: Zhang Jun et al.
, Gila, 2022) Figure 2 Specific knockout of c-Abl resulted in developmental dysmyelination and reduced OPC proliferation ( Source: Zhang Jun et al.
, Gila, 2022) The non-receptor tyrosine kinase c-Abl exerts its regulatory effect by phosphorylating downstream target proteins
.

It has been reported in the literature that changes in the phosphorylation state of transcription factor Olig2 at serine 147 affect the preference for Olig2 dimer formation and determine cell differentiation fate.
Olig2 phosphorylation at serine 10, 13 and 14 promotes neural stem cell proliferation[6-7]
.

The authors speculate that Olig2 is a potential target downstream of c-Abl in OL development.
Using co-immunoprecipitation, mass spectrometry, point mutation and other methods, they elucidated that c-Abl specifically phosphorylates the Y137 site on Olig2 and stabilizes Olig2 homologous 2 Aggregate formation (Fig.
3)
.

Figure 3 c-Abl phosphorylates the Tyr137 site of Olig2 to promote its dimerization (Source: Zhang Jun et al.
, Gila, 2022) The researchers further explored whether the c-Abl-Olig2 signaling pathway is involved in demyelinating diseases Play a role? 8-week-old WT and c-Abl CKO mice were used to construct a CPZ-induced demyelination model.
Black-gold II staining and other tests showed that CKO mice exhibited remyelination at 2 and 4 weeks after returning to normal diet.
ization delay (Figure 4)
.

This suggests that oligodendrocyte-specific knockout of c-Abl results in blocked remyelination in mice
.

Figure 4 Specific knockout of c-Abl affects remyelination, long-term inhibition of c-Abl has side effects (Source: Zhang Jun et al.
, Gila, 2022) Tyrosine kinase inhibitor nilotinib (nilotinib) It has been widely used in the treatment of chronic myeloid leukemia for nearly two decades, and the therapeutic effect is remarkable [8].
However, there are side effects such as vomiting, nausea, decreased appetite, fatigue and headache, but the cause is unknown
.

The researchers used nilotinib (25 mg/kg) to continuously gavage mice for 14 weeks, and the mice developed motor dysfunction, accompanied by a decrease in the number of OPCs and OLs (Figure 4)
.

This result may elucidate the mechanism by which nilotinib induces toxic side effects in the central nervous system
.

Figure 5 Summary of work: c-Abl mediates Olig2 phosphorylation to promote oligodendrocyte precursor cell proliferation and myelination (Source: Zhang Jun et al.
, Gila, 2022) Conclusions and discussions, inspiration and prospects This study combines biochemical, histopathological, genetic manipulation, and demyelinating disease models to focus on the role of c-Abl in oligodendrocyte development, and finds that c-Abl is specifically knocked out during normal development.
This resulted in decreased OPCs proliferation and blocked myelination; c-Abl knockout resulted in delayed remyelination in demyelinating pathological states
.

Mechanistically, the authors elucidated that c-Abl promotes Olig2 homodimerization by phosphorylating the Tyr137 site of Olig2 to maintain OPC proliferation
.

In addition, the authors also found potential neurotoxic side effects of long-term clinical use of nilotinib (a tyrosine kinase inhibitor) (Figure 5)
.

 However, there are still some unresolved questions in the study, such as: What are the downstream genes regulated by c-Abl after phosphorylation of Olig2? Is there a gap between the serine site (Ser10/13/14) and the tyrosine site of Olig2? Synergistic or antagonistic effect? This requires further research
.

 In conclusion, the study revealed the role and mechanism of the c-Abl-Olig2 signaling pathway in OPC proliferation, complemented the molecular regulation in myelination and regeneration, and provided new ideas and drugs for the prevention and treatment of hypomyelination and demyelination-related diseases target
.

Link to the original text: https://onlinelibrary.
wiley.
com/doi/10.
1002/glia.
24157 Researcher Yuan Zengqiang (photo provided by: Yuan Zengqiang Laboratory) Yuan Zengqiang, Distinguished Researcher and Doctoral Supervisor of the Brain Science Center of the Academy of Military Medical Sciences, National "Outstanding Youth", "Hundred Talents" of the Chinese Academy of Sciences, and one of the top ten outstanding young people of the Chinese Academy of Sciences
.

He has long been engaged in the research on the pathogenic mechanism and translational application of neurological diseases, focusing on energy metabolism, epigenetics and neuroinflammation regulation, analyzing the cellular and molecular mechanisms of neurodegenerative diseases and psychiatric diseases, and exploring potential targets for disease treatment
.

So far, nearly 80 papers have been published in journals such as Science, Cell, Cell Metabolism, Cell Research, Science Advances, and Molecular Psychiatry
.

This paper is supported by the National Foundation of China Key Projects (81930029, 81630026), General Projects (81971091), Youth Projects (81900227) and the Youth Project of the Key R&D Program of the Ministry of Science and Technology (2017YFA0106200)
.

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