SVZa neural stem cells differentiate into distinct lineages in response to BMP4.
Neural stem cells (NSCs) reside in the anterior portion of the forebrain subventricular zone (SVZa) and generate the progenitors which will differentiate into neurons, and via a tangential migratory pathway, known as the rostral migratory stream (RMS), migrate to the olfactory bulbs (OB). Bone morphogenetic proteins (BMPs) play significant roles in neural development at different stages and locations, but their roles have not been determined in the SVZa. To explore possible roles of BMPs in SVZa NSCs, BMP4 at various concentrations were tested for their capacity to induce SVZa NSCs. The expression of BMP4 was also examined in living cells using a reportor vector, in which the BMP4 promotor was conjugated with red fluorescent protein (RFP). In the meantime, the differentiation of SVZa NSCs was dynamically monitored by using reportor vectors of the Nestin enhancer and the promoters of TH and GFAP. In the OB, high expression of BMP4 was found using both promoter activity analysis and in situ hybridization. However, low BMP4 expression was found in the RMS and only moderate expression of BMP4 was displayed in the SVZa. The results also demonstrated that low concentrations (1-5 ng/ml) of BMP4 promoted the proliferation of SVZa NSCs but high concentrations (10-100 ng/ml) of BMP4 inhibited this proliferation. BMP4 enhanced neuron commitment before 4 days but inhibited it after 4 days. As the antagonist of BMP4, Noggin almost completely blocked all these BMP4 responses. Thus, our findings indicate that BMP4 promotes the exit from the cell cycle and triggers the differentiation of neuron progenitors in the OB. BMP4 also promotes the proliferation of the committed neuron progenitors in the RMS, but in the SVZa, BMP4 may facilitate the commitment of NSCs into astrocytes.
Liu
Shi-Yong
SY
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Zhang
Zhi-Yuan
ZY
Song
Ye-Chun
YC
Qiu
Ke-Jun
KJ
Zhang
Ke-Cheng
KC
An
Ning
N
Zhou
Zheng
Z
Cai
Wen-Qin
WQ
Yang
Hui
H
D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000235:genetics; D020547:Lateral Ventricles / Q000166:cytology*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D000097573:Red Fluorescent Protein; D000099176:Noggin Protein
D000943:Antigens, Differentiation; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D011506:Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014446:Tyrosine 3-Monooxygenase; D000097573:Red Fluorescent Protein; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C577485:Nes protein, mouse