Interactions between ICAM-5 and β1 integrins regulate neuronal synapse formation

Abstract

SummaryIntercellular adhesion molecule-5 (ICAM-5) is a dendrite-specific adhesion molecule, which functions in both the immune and nervous systems. ICAM-5 is the only negative regulator that has been identified for maturation of dendritic spines so far. Shedding of the ICAM-5 ectodomain promotes spine maturation and enhances synaptic activity. However, the mechanism by which ICAM-5 regulates spine development remains poorly understood. In this study, we found that ablation of ICAM5 expression resulted in a significant increase in the formation of synaptic contacts and the frequency of miniature excitatory post-synaptic currents, an indicator of pre-synaptic release probability. Antibodies against ICAM-5 and b1 integrins altered spine maturation. Furthermore, we found that b1 integrins serve as binding partners for ICAM-5. b1 integrins were immunoprecipitated with ICAM-5 from mouse brain and the binding region in ICAM-5 was localized to the two first Ig domains. b1 integrins were juxtaposed to filopodia tips at the early stage of synaptic formation, but as synapses matured, b1 integrins covered the mushroom spines. Loss of b1 integrins from the pre-synaptic sites affected the morphology of the post-synaptic structures. ICAM-5 ectodomain cleavage decreased or increased when the interaction between ICAM-5 and b1 integrins was potentiated or weakened, respectively, using antibodies. These results suggest that the interaction between ICAM-5 and b1 integrins is important in formation of functional synapses.

Methylome repatterning in a mouse model of Maternal PKU Syndrome

“…Abi3bp and Icam5 function in dendritic spine formation [41][42][43]. Anatomic pathology in the human MPKU brain observed aberrant 3rd cortical layer neurogenesis and deficient dendritic spines [44].…”

ECM receptors in neuronal structure, synaptic plasticity, and behavior

“…Many of the integrins present at developing and mature synapses are heterodimers containing the β1 subunit (Mortillo et al, 2012; Ning et al, 2013). In olfactory bulb axons, β1 subunit-containing integrins have been shown to interact with Semaphorin 7A (Sema7A), which is a secreted and glycosylphosphatidylinositol-anchored semaphorin expressed during neural development (Pasterkamp et al, 2003).…”

“…Recently, β1 integrins, most likely α5β1, have been shown to interact directly also with telencephalin (TLCN; aka intercellular adhesion molecule-5, ICAM-5), which is a member of the immunoglobulin superfamily of cell adhesion molecules selectively expressed in the mammalian forebrain (Conant et al, 2011; Ning et al, 2013). TLCN is enriched in the soma, dendritic shafts, dendritic filopodia, and immature dendritic spines of excitatory neurons.…”

“…TLCN is enriched in the soma, dendritic shafts, dendritic filopodia, and immature dendritic spines of excitatory neurons. Symmetrically, β1 integrins is expressed predominantly at presynaptic sites in nascent synapses (Hellwig et al, 2011; Matsuno et al, 2006; Ning et al, 2013). At early stages of synapse formation, TLCN and β1 integrins likely start forming loose and dynamic contacts between filopodia tips and axonal terminals (Conant et al, 2011; Ning et al, 2013).…”

“…Symmetrically, β1 integrins is expressed predominantly at presynaptic sites in nascent synapses (Hellwig et al, 2011; Matsuno et al, 2006; Ning et al, 2013). At early stages of synapse formation, TLCN and β1 integrins likely start forming loose and dynamic contacts between filopodia tips and axonal terminals (Conant et al, 2011; Ning et al, 2013). Notably, either deletion of cell adhesion molecules or inhibition of their interactions with function-blocking antibodies promotes structural and functional maturation of dendritic spines (Matsuno et al, 2006; Ning et al, 2013).…”