Delta/Notch signaling in glia maintains motor nerve barrier function and synaptic transmission by controlling matrix metalloproteinase expression.
Delta/Notch signaling in glia maintains motor nerve barrier function and synaptic transmission by controlling matrix metalloproteinase expression.
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DOI：
10.1073/pnas.2110097119
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发表时间：
2022-08-23
影响因子：
11.1
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中科院分区：
文献类型：
--
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We have made a surprising discovery linking Delta/Notch signaling in subperineurial glia (SPG) to the regulation of nerve ensheathment and neurotransmitter release at the Drosophila neuromuscular junction (NMJ). SPG, the counterpart of the endothelial layer in the vertebrate blood–brain barrier, form the key cellular layer that is critical for axonal ensheathment and the blood–brain barrier in Drosophila. Our findings demonstrate that Delta/Notch signaling exerts a constitutive negative inhibition on JNK signaling in SPG, thereby limiting the expression of Mmp1, a matrix metalloproteinase. SPG-specific and temporally regulated knockdown of Delta leads to breakdown of barrier function and compromises neurotransmitter release at the NMJ. Our results provide a mechanistic insight into the biology of barrier function and glia–neuron interactions. While the role of barrier function in establishing a protective, nutrient-rich, and ionically balanced environment for neurons has been appreciated for some time, little is known about how signaling cues originating in barrier-forming cells participate in maintaining barrier function and influence synaptic activity. We have identified Delta/Notch signaling in subperineurial glia (SPG), a crucial glial type for Drosophila motor axon ensheathment and the blood–brain barrier, to be essential for controlling the expression of matrix metalloproteinase 1 (Mmp1), a major regulator of the extracellular matrix (ECM). Our genetic analysis indicates that Delta/Notch signaling in SPG exerts an inhibitory control on Mmp1 expression. In the absence of this inhibition, abnormally enhanced Mmp1 activity disrupts septate junctions and glial ensheathment of peripheral motor nerves, compromising neurotransmitter release at the neuromuscular junction (NMJ). Temporally controlled and cell type–specific transgenic analysis shows that Delta/Notch signaling inhibits transcription of Mmp1 by inhibiting c-Jun N-terminal kinase (JNK) signaling in SPG. Our results provide a mechanistic insight into the regulation of neuronal health and function via glial-initiated signaling and open a framework for understanding the complex relationship between ECM regulation and the maintenance of barrier function.
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影响因子：
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