Abstract
SummaryTetraspanins are a class of evolutionarily conserved transmembrane proteins with 33 members identified in mammals that have the ability to organize specific membrane domains, named tetraspanin-enriched microdomains (TEMs). Despite the relative abundance of different tetraspanins in the CNS, few studies have explored their role at synapses. Here, we investigate the function of TSPAN5, a member of the tetraspanin superfamily for which mRNA transcripts are found at high levels in the mouse brain. We demonstrate that TSPAN5 is localized in dendritic spines of pyramidal excitatory neurons and that TSPAN5 knockdown induces a dramatic decrease in spine number because of defects in the spine maturation process. Moreover, we show that TSPAN5 interacts with the postsynaptic adhesion molecule neuroligin-1, promoting its correct surface clustering. We propose that membrane compartmentalization by tetraspanins represents an additional mechanism for regulating excitatory synapses.
Highlights
Tetraspanins are a class of transmembrane proteins evolutionarily conserved in metazoans
TSPAN5 Is Expressed in the Postsynaptic Compartment of Hippocampal Pyramidal Neurons TSPAN5 has not been studied in neurons; we confirmed its expression in mouse brain lysates obtained with strong detergents (Triton X-100 and NP40) (Figure S1A, WT lane)
Lysis of cultured hippocampal neurons during synaptogenesis (DIV 12) in a buffer containing Triton X-100 and NP40 (RIPA buffer) revealed an enrichment of TSPAN5 in the supernatant, whereas digitonin led to its concentration in the pellet (Figure S3A). This result supports the presence of TSPAN5 tetraspanin-enriched microdomains (TEMs) in immature neurons. To investigate if these domains are key for dendritic spine formation, we examined the presence in TEMs of NLG1 and the AMPAR subunit GluA2, two crucial players in dendritic spine formation and excitatory synapses function, respectively (Bassani et al, 2009, 2013; Chih et al, 2005; Hall and Ghosh, 2008)
Summary
Tetraspanins are a class of transmembrane proteins evolutionarily conserved in metazoans. 33 mammalian tetraspanins have been described to act in cell-cell adhesion, cell motility and proliferation, immunity, and nervous system development (Hemler, 2005), but there is little work on their synaptic function (Bassani et al, 2012; Murru et al, 2017, 2018), their supramolecular organization at synapses is unknown. The role of these proteins in membrane domain assembly and in cell-cell adhesion supports a possible function in synapse formation and activity
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