Regulation of dendritic branching and spine maturation by semaphorin3A-Fyn signaling.
A member of semaphorin family, semaphorin3A (Sema3A), acts as a chemorepellent or chemoattractant on a wide variety of axons and dendrites in the development of the nervous systems. We here show that Sema3A induces clustering of both postsynaptic density-95 (PSD-95) and presynaptic synapsin I in cultured cortical neurons without changing the density of spines or filopodia. Neuropilin-1 (NRP-1), a receptor for Sema3A, is present on both axons and dendrites. When the cultured neurons are exposed to Sema3A, the cluster size of PSD-95 is markedly enhanced, and an extensive colocalization of PSD-95 and NRP-1 or actin-rich protrusion is seen. The effects of Sema3A on spine morphology are blocked by PP2, an Src type tyrosine kinase inhibitor, but not by the PP3, the inactive-related compound. In the cultured cortical neurons from fyn(-/-) mice, dendrites bear few spines, and Sema3A does not induce PSD-95 cluster formation on the dendrites. Sema3A and its receptor genes are highly expressed during the synaptogenic period of postnatal days 10 and 15. The cortical neurons in layer V, but not layer III, show a lowered density of synaptic bouton-like structure on dendrites in sema3A- and fyn-deficient mice. The neurons of the double-heterozygous mice show the lowered spine density, whereas those of single heterozygous mice show similar levels of the spine density as the wild type. These findings suggest that the Sema3A signaling pathway plays an important role in the regulation of dendritic spine maturation in the cerebral cortex neurons.
Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Asa
A
Morita
Naoya
N
Yamashita
Yukio
Y
Sasaki
Yutaka
Y
Uchida
Oumi
O
Nakajima
Fumio
F
Nakamura
Takeshi
T
Yagi
Masahiko
M
Taniguchi
Hiroshi
H
Usui
Ritsuko
R
Katoh-Semba
Kohtaro
K
Takei
Yoshio
Y
Goshima
D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000166:cytology*; D003712:Dendrites / Q000187:drug effects* / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D005838:Genotype; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009024:Morphogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D017729:Presynaptic Terminals / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D040121:Semaphorin-3A / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D016704:Synapsins / Q000378:metabolism*
C509621:4-amino-7-phenylpyrazol(3,4-d)pyrimidine; C412373:AG 1879; D000199:Actins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D040121:Semaphorin-3A; D016704:Synapsins; D051076:Proto-Oncogene Proteins c-fyn; D051528:Guanylate Kinases