Abstract
Introduction: Podoplanin is a cell-surface glycoprotein constitutively expressed in the brain and implicated in human brain tumorigenesis. The intrinsic function of podoplanin in brain neurons remains however uncharacterized.Materials and methods: Using an established podoplanin-knockout mouse model and electrophysiological, biochemical, and behavioral approaches, we investigated the brain neuronal role of podoplanin.Results: Ex-vivo electrophysiology showed that podoplanin deletion impairs dentate gyrus synaptic strengthening. In vivo, podoplanin deletion selectively impaired hippocampus-dependent spatial learning and memory without affecting amygdala-dependent cued fear conditioning. In vitro, neuronal overexpression of podoplanin promoted synaptic activity and neuritic outgrowth whereas podoplanin-deficient neurons exhibited stunted outgrowth and lower levels of p-Ezrin, TrkA, and CREB in response to nerve growth factor (NGF). Surface Plasmon Resonance data further indicated a physical interaction between podoplanin and NGF.Discussion: This work proposes podoplanin as a novel component of the neuronal machinery underlying neuritogenesis, synaptic plasticity, and hippocampus-dependent memory functions. The existence of a relevant cross-talk between podoplanin and the NGF/TrkA signaling pathway is also for the first time proposed here, thus providing a novel molecular complex as a target for future multidisciplinary studies of the brain function in the physiology and the pathology.Key messagesPodoplanin, a protein linked to the promotion of human brain tumors, is required in vivo for proper hippocampus-dependent learning and memory functions.Deletion of podoplanin selectively impairs activity-dependent synaptic strengthening at the neurogenic dentate-gyrus and hampers neuritogenesis and phospho Ezrin, TrkA and CREB protein levels upon NGF stimulation.Surface plasmon resonance data indicates a physical interaction between podoplanin and NGF. On these grounds, a relevant cross-talk between podoplanin and NGF as well as a role for podoplanin in plasticity-related brain neuronal functions is here proposed.
Highlights
Podoplanin is a cell-surface glycoprotein constitutively expressed in the brain and implicated in human brain tumorigenesis
A podoplanin knockout mouse line that had been previously studied in the context of vascular physiology [12], as well as podoplanin-overexpression experiments, were used as a model to study the role of podoplanin in the mammalian brain neuron
Other groups have shown that alterations of hippocampus-dependent memory functions that are associated with disruptions in synaptic potentiation in the dentate gyrus can occur without detectable impairments in CA3-Schaffer Collateral-CA1 [21]
Summary
Podoplanin is a cell-surface glycoprotein constitutively expressed in the brain and implicated in human brain tumorigenesis. Discussion: This work proposes podoplanin as a novel component of the neuronal machinery underlying neuritogenesis, synaptic plasticity, and hippocampus-dependent memory functions. We provide the first experimental evidence indicating that podoplanin is implicated in the regulation of brain neuronal outgrowth, synaptic plasticity, and hippocampus-dependent learning and memory. For the first time, we describe that podoplanin can physically interact with NGF, a neurotrophin importantly implicated in the regulation of hippocampus-mediated memory storage [13], in the pathophysiology of brain tumors [14,15] and in Alzheimer’s disease [16,17,18,19]. Our data propose podoplanin as a novel molecular component of the cellular machinery regulating neuritogenesis and memory-related synaptic plasticity through a mechanism involving physical interaction with NGF and modulation of p-Ezrin, TrkA, and CREB protein levels
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