Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells.
In the mammalian brain, neurogenesis continues only in few regions of the forebrain. The molecular signals governing neurogenesis in these unique neurogenic niches, however, are still ill defined. Here, we show that bone morphogenic protein (BMP)-mediated signaling is active in adult neural stem cells and is crucial to initiate the neurogenic lineage in the adult mouse subependymal zone. Conditional deletion of Smad4 in adult neural stem cells severely impairs neurogenesis, and this is phenocopied by infusion of Noggin, an extracellular antagonist of BMP. Smad4 deletion in stem, but not progenitor cells, as well as Noggin infusion lead to an increased number of Olig2-expressing progeny that migrate to the corpus callosum and differentiate into oligodendrocytes. Transplantation experiments further verified the cell-autonomous nature of this phenotype. Thus, BMP-mediated signaling via Smad4 is required to initiate neurogenesis from adult neural stem cells and suppress the alternative fate of oligodendrogliogenesis.
Colak
Dilek
D
Helmhotz Center Munich, Institute for Stem Cell Research, 85764 Neuherberg/Munich, Germany.
Mori
Tetsuji
T
Brill
Monika S
MS
Pfeifer
Alexander
A
Falk
Sven
S
Deng
Chuxia
C
Monteiro
Rui
R
Mummery
Christine
C
Sommer
Lukas
L
Götz
Magdalena
M
D053687:Adult Stem Cells / Q000502:physiology*; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017690:Cell Transplantation / Q000379:methods; D004965:Estrogen Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051901:Smad4 Protein / Q000172:deficiency / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D000099176:Noggin Protein
D027322:Amino Acid Transport System X-AG; D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D001973:Bromodeoxyuridine; D002352:Carrier Proteins; D004965:Estrogen Antagonists; D005904:Glial Fibrillary Acidic Protein; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051901:Smad4 Protein; D013629:Tamoxifen; D014157:Transcription Factors; D000099176:Noggin Protein; C088334:Distal-less homeobox proteins; C512773:Olig2 protein, mouse; C490810:Smad4 protein, mouse