LRP2 in ependymal cells regulates BMP signaling in the adult neurogenic niche.
The microenvironment of growth factors in the subependymal zone (SEZ) of the adult brain provides the instructive milieu for neurogenesis to proceed in this germinal niche. In particular, tight regulation of bone morphogenetic protein (BMP) signaling is essential to balance proliferative and non-proliferative cell fate specification. However, the regulatory pathways that control BMP signaling in the SEZ are still poorly defined. We demonstrate that LRP2, a clearance receptor for BMP4 is specifically expressed in ependymal cells of the lateral ventricles in the adult brain. Intriguingly, expression is restricted to the ependyma that faces the stem cell niche. Expression is not seen in ependyma elsewhere in the lateral ventricles or in the dentate gyrus, the second major neurogenic zone of the adult brain. We further show that lack of LRP2 expression in adult mice results in impaired proliferation of neural precursor cells in the SEZ resulting in decreased numbers of neuroblasts reaching the olfactory bulb. Reduced neurogenesis coincides with increased BMP4 expression and enhanced activation of downstream mediators phospho-SMAD1/5/8 and ID3 in the stem cell niche. Our findings suggest a novel mechanism whereby LRP2-mediated catabolism of BMP4 in the ependyma modulates the microenvironment of the SEZ and enables adult neurogenesis to proceed.
Gajera
Chandresh R
CR
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, D-13125 Berlin, Germany.
Emich
Helena
H
Lioubinski
Oleg
O
Christ
Annabel
A
Beckervordersandforth-Bonk
Ruth
R
Yoshikawa
Kazuaki
K
Bachmann
Sebastian
S
Christensen
Erik Ilsø
EI
Götz
Magdalena
M
Kempermann
Gerd
G
Peterson
Andrew S
AS
Willnow
Thomas E
TE
Hammes
Annette
A
D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004805:Ependyma / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D018034:Olfactory Receptor Neurons / Q000166:cytology; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D055153:Stem Cell Niche / Q000378:metabolism*
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D051796:Inhibitor of Differentiation Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D009363:Neoplasm Proteins; D051785:Smad Proteins; C075640:ID3 protein, human