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Enhancing myelinogenesis through LIN28A rescues impaired cognition in PWMI mice
Xuan Wu1, Zhechun Hu2,3,4, Huimin Yue5
1Center of Stem Cell and Regenerative Medicine, and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Insights
Preterm white matter injury (PWMI) impairs cognitive function by affecting oligodendrocyte precursor cells (OPCs). Restoring LIN28A in OPCs promotes myelinogenesis and rescues cognitive deficits in PWMI mouse models.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Biology
Background:
- Preterm white matter injury (PWMI) in newborns leads to motor and cognitive impairments.
- PWMI is linked to impaired oligodendrocyte precursor cell (OPC) differentiation and maturation.
- The precise mechanisms underlying PWMI pathogenesis remain largely unknown.
Purpose of the Study:
- To investigate the role of RNA-binding protein LIN28A in OPC differentiation and myelinogenesis.
- To explore LIN28A as a potential therapeutic target for PWMI.
Main Methods:
- Analyzed LIN28A expression in OPCs using RNAscope.
- Generated knockout and overexpression mouse models for Lin28a in OPCs.
- Assessed cognitive functions through behavioral tests.
Main Results:
- LIN28A expression was reduced in OPCs from a PWMI mouse model.
- Lin28a knockout in OPCs led to impaired OPC differentiation, reduced myelination, and cognitive deficits.
- LIN28A supplementation promoted OPC differentiation and myelination, rescuing cognitive function in PWMI mice.
Conclusions:
- LIN28A is crucial for regulating postnatal myelinogenesis.
- Overexpressing LIN28A in OPCs can ameliorate cognitive deficits in PWMI by enhancing myelinogenesis.
- LIN28A represents a promising therapeutic strategy for treating PWMI.
Background:
In premature newborn infants, preterm white matter injury (PWMI) causes motor and cognitive disabilities. Accumulating evidence suggests that PWMI may result from defected differentiation of oligodendrocyte precursor cells (OPCs) and impaired maturation of oligodendrocytes. However, the underlying mechanisms remain unclear.
Methods:
Using RNAscope, we analyzed the expression level of RNA-binding protein LIN28A in individual OPCs. Knockout of one or both alleles of Lin28a in OPCs was achieved by administrating tamoxifen to NG2CreER::Ai14::Lin28aflox/+ or NG2CreER::Ai14::Lin28aflox/flox mice. Lentivirus expressing FLEX-Lin28a was used in NG2CreER mice to overexpress LIN28A in OPCs. A series of behavioral tests were performed to assess the cognitive functions of mice. Two-tailed unpaired t-tests was carried out for statistical analysis between groups.
Results:
We found that the expression of Lin28a was decreased in OPCs in a PWMI mouse model. Knockout of one or both alleles of Lin28a in OPCs postnatally resulted in reduced OPC differentiation, decreased myelinogenesis and impaired cognitive functions. Supplementing LIN28A in OPCs postnatally was able to promote OPC differentiation and enhance myelinogenesis, thus rescuing the cognitive functions in PWMI mice.
Conclusion:
Our study reveals that LIN28A is critical in regulating postnatal myelinogenesis. Overexpression of LIN28A in OPCs rescues cognitive deficits in PWMI mice by promoting myelinogenesis, thus providing a potential strategy for the treatment of PWMI.
