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PMID: 23787772 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

The Journal of comparative neurology ·Vol. 521 ·No. 14 ·2013-10-01 ·Pages 3241-59

Eagleson KL, Milner TA, Xie Z, Levitt P

Abstract

MET, a replicated autism risk gene, encodes a pleiotropic receptor tyrosine kinase implicated in multiple cellular processes during development and following injury. Previous studies suggest that Met modulates excitatory synapse development in the neocortex and hippocampus, although the underlying mechanism is unknown. The peak of Met expression corresponds to the period of process outgrowth and synaptogenesis, with robust expression in hippocampal and neocortical neuropil. Resolving whether neuropil expression represents presynaptic, postsynaptic or glial localization provides insight into potential mechanisms of Met action. The subcellular distribution of Met was characterized using complementary ultrastructural, in situ proximity ligation assay (PLA), and biochemical approaches. At postnatal day (P) 7, immunoelectron microscopy revealed near-equivalent proportions of Met-immunoreactive pre- (axons and terminals) and postsynaptic (dendritic shafts and spines) profiles in the stratum radiatum in the hippocampal CA1 region. Staining was typically in elements in which the corresponding pre- or postsynaptic apposition was unlabeled. By P21, Met-immunoreactive presynaptic profiles predominated and ~20% of Met-expressing profiles were glial. A different distribution of Met-immunoreactive profiles was observed in layer V of somatosensory cortex: Met-labeled spines were rare and a smaller proportion of glial profiles expressed Met. Strikingly, Met-immunoreactive presynaptic profiles predominated over postsynaptic profiles as early as P7. PLA analysis of neurons in vitro and biochemical analysis of tissue subsynaptic fractions confirmed the localization of Met in specific synaptic subcompartments. The study demonstrates that Met is enriched at synapses during development and its activation may modulate synapse formation and stability through both pre- and postsynaptic mechanisms.

Keywords
axon dendritic spine hepatocyte growth factor receptor tyrosine kinase synaptogenesis
MeSH Terms
Age Factors Animals Animals, Newborn Dendrites/metabolism,ultrastructure Embryo, Mammalian Female Gene Expression Regulation, Developmental/physiology Hippocampus/cytology,embryology,growth & development Male Mice Mice, Inbred C57BL Microscopy, Immunoelectron Neocortex/cytology,embryology,growth & development Neuropil/metabolism,ultrastructure Pregnancy Presynaptic Terminals/metabolism,ultrastructure Receptor Protein-Tyrosine Kinases/genetics,metabolism,ultrastructure Subcellular Fractions/metabolism Synapses/metabolism,ultrastructure
Chemicals
Receptor Protein-Tyrosine Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Eagleson Kathie L
Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, California 90033, USA. [email protected]
Milner Teresa A
Xie Zhihui
Levitt Pat
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Article Info
Journal
The Journal of comparative neurology
Abbr.
J Comp Neurol
ISSN
1096-9861
DOI
10.1002/cne.23343
Email
[email protected]
Published
2013-10-01
Pages
3241-59
Language
English
Region
United States
NLM ID
0406041
PMCID
PMC3942873
Subset
IM
Grants
NIDA NIH HHS · NIH R01 DA08259 · United States
NHLBI NIH HHS · R01 HL098351 · United States
NIMH NIH HHS · R01 MH067842 · United States
NHLBI NIH HHS · P01 HL096571 · United States
NHLBI NIH HHS · HL 098351 · United States
NIDA NIH HHS · R01 DA008259 · United States
External Links
PubMed source DOI: 10.1002/cne.23343 PMC Full Text View journal details
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