In vivo proximity proteomics of nascent synapses reveals a novel regulator of cytoskeleton-mediated synaptic maturation

Erin F. Spence, Shataakshi Dube, Akiyoshi Uezu, Margaret Locke, Erik J. Soderblom and Scott H. Soderling ()
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Erin F. Spence: Duke University Medical Center
Shataakshi Dube: Duke University Medical Center
Akiyoshi Uezu: Duke University Medical Center
Margaret Locke: Duke University Medical Center
Erik J. Soderblom: Duke University Medical Center
Scott H. Soderling: Duke University Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Excitatory synapse formation during development involves the complex orchestration of both structural and functional alterations at the postsynapse. However, the molecular mechanisms that underlie excitatory synaptogenesis are only partially resolved, in part because the internal machinery of developing synapses is largely unknown. To address this, we apply a chemicogenetic approach, in vivo biotin identification (iBioID), to discover aspects of the proteome of nascent synapses. This approach uncovered sixty proteins, including a previously uncharacterized protein, CARMIL3, which interacts in vivo with the synaptic cytoskeletal regulator proteins SrGAP3 (or WRP) and actin capping protein. Using new CRISPR-based approaches, we validate that endogenous CARMIL3 is localized to developing synapses where it facilitates the recruitment of capping protein and is required for spine structural maturation and AMPAR recruitment associated with synapse unsilencing. Together these proteomic and functional studies reveal a previously unknown mechanism important for excitatory synapse development in the developing perinatal brain.

Date: 2019
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DOI: 10.1038/s41467-019-08288-w

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