Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus

Eagleson, Kathie L.; Milner, Teresa A.; Xie, Zhihui; Levitt, Pat

doi:10.1002/cne.23343

Cited by 34 publications

(44 citation statements)

References 81 publications

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“…SDS-PAGE and Western blotting were performed as described previously (Eagleson et al, 2013), with the following modifications. For both crude membrane and in vitro assays, samples covering the entire time course undergoing the same treatment were analyzed on duplicate blots to measure the kinetics of activation following addition of HGF.…”

Section: Methodsmentioning

confidence: 99%

“…A comprehensive map of MET transcript and protein expression in the mouse forebrain revealed that MET is enriched in neocortex, hippocampus and subcortical limbic regions, with expression peaking during the period of process outgrowth and synaptogenesis and waning during synapse refinement (Judson et al, 2009; Judson et al, 2011; Qiu et al, 2014). Further, over this period, MET is expressed almost exclusively in excitatory projection neurons (Eagleson et al, 2011) and is enriched in both pre- and postsynaptic compartments (Eagleson et al, 2013). Comparative analyses in primate confirmed the conservation of MET expression temporally, with peak levels observed during axon outgrowth and synapse formation, indicating a similar developmental role in the rodent and primate forebrain.…”

Section: Introductionmentioning

confidence: 99%

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Distinct intracellular signaling mediates C‐MET regulation of dendritic growth and synaptogenesis

Eagleson

Lane

McFadyen‐Ketchum

et al. 2016

Developmental Neurobiology

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Hepatocyte growth factor (HGF) activation of the MET receptor tyrosine kinase influences multiple neurodevelopmental processes. Evidence from human imaging and mouse models shows that, in the forebrain, disruptions in MET signaling alter circuit formation and function. One likely means of modulation is by controlling neuron maturation. Here, we examined the signaling mechanisms through which MET exerts developmental effects in the neocortex. In situ hybridization revealed that hgf is located near MET-expressing neurons, including deep neocortical layers and periventricular zones. Western blot analyses of neocortical crude membranes demonstrated that HGF-induced MET autophosphorylation peaks during synaptogenesis, with a striking reduction in activation between P14 and P17 just prior to pruning. In vitro analysis of postnatal neocortical neurons assessed the roles of intracellular signaling following MET activation. There is rapid, HGF-induced phosphorylation of MET, ERK1/2 and Akt that is accompanied by two major morphological changes increases in total dendritic growth and synapse density. Selective inhibition of each signaling pathway altered only one of the two distinct events. MAPK/ERK pathway inhibition significantly reduced the HGF-induced increase in dendritic length, but had no effect on synapse density. In contrast, inhibition of the PI-3K/Akt pathway reduced HGF-induced increases in synapse density, with no effect on dendritic length. The data reveal a key role for MET activation during the period of neocortical neuron growth and synaptogenesis, with distinct biological outcomes mediated via discrete MET-linked intracellular signaling pathways in the same neurons.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct intracellular signaling mediates C‐MET regulation of dendritic growth and synaptogenesis

Eagleson

Lane

McFadyen‐Ketchum

et al. 2016

Developmental Neurobiology

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“…The PLA method and quantitative analysis is described in (37) and in detail in supplemental methods.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, cortical areal expression patterns vary significantly between rodent and primate (32, 34, 35). MET is expressed in excitatory neocortical neurons and enriched in growing forebrain axons and synapses (36, 37), with phosphorylation occurring mostly in the neuropil and not in axon tracts (38). Accumulating human and animal model data demonstrate an important role for MET in circuit development.…”

Section: Introductionmentioning

confidence: 99%

Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse

Baker

Eagleson

et al. 2016

Biological Psychiatry

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Background Atypical synapse development and plasticity are implicated in many neurodevelopmental disorders (NDDs). NDD-associated, high confidence risk genes have been identified, yet little is known about functional relationships at the level of protein-protein interactions, which are the dominant molecular bases responsible for mediating circuit development. Methods Proteomics in three independent developing neocortical synaptosomal preparations identified putative interacting proteins of the ligand-activated MET receptor tyrosine kinase, an autism risk gene that mediates synapse development. The candidates were translated into interactome networks and analyzed bioinformatically. Additionally, three independent quantitative proximity ligation assays (PLA) in cultured neurons and four independent immunoprecipitation analyses of synaptosomes validated protein interactions. Results Approximately 11% (8/72) of MET-interacting proteins, including SHANK3, SYNGAP1 and GRIN2B, are associated with NDDs. Proteins in the MET interactome were translated into a novel MET interactome network based on human protein-protein interaction databases. High confidence genes from different NDD datasets that encode synaptosomal proteins were analyzed for being enriched in MET interactome proteins. This was found for autism, but not schizophrenia, bipolar disorder, major depressive disorder or attentional deficit hyperactivity disorder. There is correlated gene expression between MET and its interactive partners in developing human temporal and visual neocortices, but not with highly expressed genes that are not in the interactome. PLA and biochemical analyses demonstrate that MET-protein partner interactions are dynamically regulated by receptor activation. Conclusions The results provide a novel molecular framework for deciphering the functional relations of key regulators of synaptogenesis that contribute to both typical cortical development and to NDDs.

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“…Primary cultures of neocortical neurons were established as described previously from our laboratory (Eagleson et al, 2013), using whole cerebral hemispheres (without the hippocampus and olfactory bulb) harvested from embryonic day (E) 18.5 mice. For each culturing session, tissue from a single litter, including male and female embryos, was pooled.…”

Section: Methodsmentioning

confidence: 99%

Positive regulation of neocortical synapse formation by the Plexin-D1 receptor

2015

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Synapse formation is a critical process during neural development and is coordinated by multiple signals. Several lines of evidence implicate the Plexin-D1 receptor in synaptogenesis. Studies have shown that Plexin-D1 signaling is involved in synaptic specificity and synapse formation in spinal cord and striatum. Expression of Plexin-D1 and its principal neural ligand, Sema3E, by neocortical neurons is temporally and spatially regulated, reaching the highest level at the time of synaptogenesis in mice. In this study, we examined the function of Plexin-D1 in synapse formation by primary neocortical neurons in vitro. A novel, automated image analysis method was developed to quantitate synapse formation under baseline conditions and with manipulation of Plexin-D1 levels. shRNA and overexpression manipulations caused opposite changes, with reduction resulting in less synapse formation, an effect distinct from that reported in the striatum. The data indicate that Plexin-D1 operates in a cell context-specific fashion, mediating different synaptogenic outcomes depending upon neuron type.

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Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus

Cited by 34 publications

References 81 publications

Distinct intracellular signaling mediates C‐MET regulation of dendritic growth and synaptogenesis

Distinct intracellular signaling mediates C‐MET regulation of dendritic growth and synaptogenesis

Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse

Positive regulation of neocortical synapse formation by the Plexin-D1 receptor

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