Abstract
In the immune system, Major Histocompatibility Complex class I (MHC-I) molecules are located on the surface of most nucleated cells in vertebrates where they mediate immune responses. Accumulating evidence indicates that MHC-I molecules are also expressed in the central nervous system (CNS) where they play important roles that are significantly different from their immune functions. Classical MHC-I molecules are temporally and spatially expressed in the developing and adult CNS, where they participate in the synaptic formation, remodeling and plasticity. Therefore, clarifying the regulation of MHC-I expression is necessary to develop an accurate understanding of its function in the CNS. Here, we show that microRNA 34a (miR34a), a brain enriched noncoding RNA, is temporally expressed in developing hippocampal neurons, and its expression is significantly increased after MHC-I protein abundance is decreased in the hippocampus. Computational algorithms identify putative miR34a target sites in the 3′UTR of MHC-I mRNA, and here we demonstrate direct targeting of miR34a to MHC-I mRNA using a dual-luciferase reporter assay system. MiR34a targeting can decrease constitutive MHC-I expression in both Neuro-2a neuroblastoma cells and primary hippocampal neurons. Finally, miR34a mediated reduction of MHC-I results in increased dendritic growth and branching in cultured hippocampal neurons. Taken together, our findings identify miR34a as a novel regulator of MHC-I for shaping neural morphology in developing hippocampal neurons.
Highlights
For a long time, the central nervous system (CNS) has been considered to be ‘‘immuneprivileged.’’ This view, has changed following the identification of classical immune molecules such as cytokines, complement, and major histocompatibility complex (MHC) proteins in the healthy, uninfected CNS (Joly et al, 1991)
There was an increase of H-2Kb and H-2Db proteins from postnatal day 0 (P0) to P15 before it decreased to a relatively low level, despite a sustained increased H-2Kb and H-2Db messenger RNA transcripts (mRNAs) from P0 to P60, suggesting post-transcriptional regulation mechanisms such as miRNAs might be involved after P15
These results showed that the binding of microRNA 34a (miR34a) to Major Histocompatibility Complex class I (MHC-I) mRNA was dependent on the 3 UTR sequence of H-2Db or H-2Kb and miR34a could decrease MHC-I expression
Summary
The central nervous system (CNS) has been considered to be ‘‘immuneprivileged.’’ This view, has changed following the identification of classical immune molecules such as cytokines, complement, and major histocompatibility complex (MHC) proteins in the healthy, uninfected CNS (Joly et al, 1991). In the developing cerebellum and hippocampus, levels of MHC-I protein gradually increase from postnatal day 0 (P0) to a peak value at P15, a crucial period for synaptic remodeling and plasticity. After completing their functions, protein abundance becomes significantly reduced with age until neuronal MHC-I proteins can no longer be detected after P60. A similar expression pattern of MHC-I proteins is observed during human CNS development (Zhang et al, 2013a,b) This evidence suggests that the expression of MHC-I proteins is tightly regulated in the developing CNS due to their role in important neurodevelopmental events. Due to this discrepancy between protein abundance and mRNA levels during development, the complex regulation of MHC-I expression at the transcriptional and post-transcriptional level needs to be further investigated
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