mGLU3 metabotropic glutamate receptors modulate the differentiation of SVZ-derived neural stem cells towards the astrocytic lineage.
Neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of postnatal mice, and cultured as neurospheres, expressed functional mGlu3 receptors. Following mitogen withdrawal and plating onto poly-ornitine-coated dishes, cells dissociated from the neurospheres differentiated into GFAP(+) astrocytes (about 85%), and a small percentage of beta-III tubulin(+)-neurons and O1(+)-oligodendrocytes. Activation of mGlu3 receptors with LY379268 (100 nM, applied every other day), during the differentiation period, impaired astrocyte differentiation, favoring the maintenance in culture of proliferating progenitors co-expressing GFAP with the immature markers, Sox1 and nestin. Co-treatment with the preferential mGlu2/3 receptor antagonist, LY341495 (100 nM), reversed this effect. We examined whether mGlu3 receptors could modulate the canonical signaling pathway activated by bone morphogenic proteins (BMPs), which are known to promote astrocyte differentiation of SVZ/NSCs. An acute challenge of cells isolated from the neurospheres with BMP4 (100 ng/mL) led to phosphorylation and nuclear translocation of the transcription factors, Smads. This effect was largely attenuated by the mGlu2/3 receptor agonist, LY379268. The interaction of mGlu3 and BMP4 receptors was mediated by the activation of the mitogen-activated protein kinase (MAPK) pathway. Accordingly, LY379268 failed to affect BMP receptor signaling when combined with the MAPK kinase inhibitor, UO-126 (30 muM). These data raise the intriguing possibility that glutamate regulates differentiation of SVZ/NSCs by activating mGlu3 receptors.
Ciceroni
C
C
I.R.C.C.S. San Raffaele Pisana, Rome, Italy.
Mosillo
P
P
Mastrantoni
E
E
Sale
P
P
Ricci-Vitiani
L
L
Biagioni
F
F
Stocchi
F
F
Nicoletti
F
F
Melchiorri
D
D
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism / Q000494:pharmacology; D052004:Bone Morphogenetic Protein Receptors / Q000819:agonists / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D018874:Spheroids, Cellular; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology / Q000378:metabolism*
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D018094:Receptors, Metabotropic Glutamate; D055748:SOXB1 Transcription Factors; D051785:Smad Proteins; C098693:Sox1 protein, mouse; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; D052004:Bone Morphogenetic Protein Receptors