ABSTRACT
In neurons, the microtubule (MT) cytoskeleton forms the basis for long-distance protein transport from the cell body into and out of dendrites and axons. To maintain neuronal polarity, the axon initial segment (AIS) serves as a physical barrier, separating the axon from the somatodendritic compartment and acting as a filter for axonal cargo. Selective trafficking is further instructed by axonal enrichment of MT post-translational modifications, which affect MT dynamics and the activity of motor proteins. Here, we compared two knockout mouse lines lacking the respective enzymes for MT tyrosination and detyrosination, and found that both knockouts led to a shortening of the AIS. Neurons from both lines also showed an increased immobile fraction of endolysosomes present in the axon, whereas mobile organelles displayed shortened run distances in the retrograde direction. Overall, our results highlight the importance of maintaining the balance of tyrosinated and detyrosinated MTs for proper AIS length and axonal transport processes.
Subject(s)
Axonal Transport , Lysosomes , Mice, Knockout , Microtubules , Tyrosine , Animals , Microtubules/metabolism , Tyrosine/metabolism , Lysosomes/metabolism , Mice , Axons/metabolism , Endosomes/metabolism , Neurons/metabolismABSTRACT
A Disintegrin And Metalloproteinase 10 (ADAM10) plays a pivotal role in shaping neuronal networks by orchestrating the activity of numerous membrane proteins through the shedding of their extracellular domains. Despite its significance in the brain, the specific cellular localization of ADAM10 remains not well understood due to a lack of appropriate tools. Here, using a specific ADAM10 antibody suitable for immunostainings, we observed that ADAM10 is localized to presynapses and especially enriched at presynaptic vesicles of mossy fiber (MF)-CA3 synapses in the hippocampus. These synapses undergo pronounced frequency facilitation of neurotransmitter release, a process that play critical roles in information transfer and neural computation. We demonstrate, that in conditional ADAM10 knockout mice the ability of MF synapses to undergo this type of synaptic plasticity is greatly reduced. The loss of facilitation depends on the cytosolic domain of ADAM10 and association with the calcium sensor synaptotagmin 7 rather than ADAM10's proteolytic activity. Our findings unveil a new role of ADAM10 in the regulation of synaptic vesicle exocytosis.
Subject(s)
ADAM10 Protein , Amyloid Precursor Protein Secretases , Membrane Proteins , Mice, Knockout , Neuronal Plasticity , Synaptic Vesicles , Animals , ADAM10 Protein/metabolism , ADAM10 Protein/genetics , Neuronal Plasticity/physiology , Amyloid Precursor Protein Secretases/metabolism , Amyloid Precursor Protein Secretases/genetics , Membrane Proteins/metabolism , Membrane Proteins/genetics , Mice , Synaptic Vesicles/metabolism , Mice, Inbred C57BL , Synapses/metabolism , Mossy Fibers, Hippocampal/metabolism , Hippocampus/metabolism , Exocytosis/physiology , Presynaptic Terminals/metabolism , Synaptic Transmission , Synaptotagmins/metabolism , Synaptotagmins/geneticsABSTRACT
Non-coding RNAs (ncRNAs) are highly plastic RNA molecules that can sequester cellular proteins and other RNAs, serve as transporters of cellular cargo and provide spatiotemporal feedback to the genome. Mounting evidence indicates that ncRNAs are central to biology, and are critical for neuronal development, metabolism and intra- and intercellular communication in the brain. Their plasticity arises from state-dependent dynamic structure states that can be influenced by cell type and subcellular environment, which can subsequently enable the same ncRNA with discrete functions in different contexts. Here, we highlight different classes of brain-enriched ncRNAs, including microRNA, long non-coding RNA and other enigmatic ncRNAs, that are functionally important for both learning and memory and adaptive immunity, and describe how they may promote cross-talk between these two evolutionarily ancient biological systems.