MiR34a Regulates Neuronal MHC Class I Molecules and Promotes Primary Hippocampal Neuron Dendritic Growth and Branching

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.

Tight Regulation of Major Histocompatibility Complex I for the Spatial and Temporal Expression in the Hippocampal Neurons

“…We confirmed that NLRC5 was responsible for promoting constitutive transcription of MHC I gene, and Ca 2+ -regulated signal transduction cascades were important for relaying membrane activity to upregulated MHC I expression in hippocampal neurons (Lv et al, 2015;Li et al, 2020). We also found that miR34a, which increased dramatically after P15, can decrease MHC I expression, suggesting that it contributed to divergent expression of MHC I mRNA and protein expression after P15 (Hu et al, 2020). Although some mechanisms have been discovered, the information about the pathways that are responsible for temporal neuronal MHC I expression is still very limited.…”

“…As we expected, miR-34a showed the ability to regulate MHC I expression in cultured hippocampus neurons. Since MHC I mRNA and protein expression were both decreased upon enhanced expression of miR-34a, we cannot tell whether miR-34a exerts its function through reducing the stability of MHC I mRNA or inhibiting the protein translation (Hu et al, 2020). However, additional in vivo data exploring the regulation of MHC I by miR-34a are still needed.…”

Food reward induction of rhythmic clock gene expression in the prefrontal cortex of rats is accompanied by changes in miR‐34a‐5p expression

“…Although the miR-34 family has been more frequently studied for its oncostatic functions (Zhang et al, 2019), it belongs among the brain-enriched miRNAs with a well-described role in synaptic modulation (Berentsen et al, 2020;Gal-Ben-Ari et al, 2012;Hu et al, 2020;Wibrand et al, 2010Wibrand et al, , 2012Zhang & Bramham, 2021). A regulatory role of miR-34a-5p in neurodevelopmental and neuropathological processes has been convincingly demonstrated (Chua & Tang, 2019;Kinoshita et al, 2020).…”

Synaptic Plasticity Conveyed by the Intracellular Domain of Major Histocompatibility Class-I Proteins

“…Although the central nervous system (CNS) has long been considered an "immunologically privileged" organ, MHC-I is expressed in neurons under normal physiological conditions (1)(2)(3)(4). In the brain, MHC-I has been found to play a role in synaptic plasticity, notably in dendrite morphogenesis and synapse pruning, (2,5). Indeed, in the absence of stable surface MHC-I, synapse density is signi cantly increased (2,(6)(7)(8)(9), and memory and learning is impaired (10)(11)(12)(13).…”