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Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis.

Kawaguchi D, Furutachi S, Kawai H, Hozumi K, Gotoh Y - Nat Commun (2013)

Bottom Line: Dll1 protein is induced in activated NSCs and segregates to one daughter cell during mitosis.Dll1-expressing cells reside in close proximity to quiescent NSCs, suggesting a feedback signal for NSC maintenance by their sister cells and progeny.Our data suggest a model in which NSCs produce their own niche cells for their maintenance through asymmetric Dll1 inheritance at mitosis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.

ABSTRACT
Stem cells often divide asymmetrically to produce one stem cell and one differentiating cell, thus maintaining the stem cell pool. Although neural stem cells (NSCs) in the adult mouse subventricular zone have been suggested to divide asymmetrically, intrinsic cell fate determinants for asymmetric NSC division are largely unknown. Stem cell niches are important for stem cell maintenance, but the niche for the maintenance of adult quiescent NSCs has remained obscure. Here we show that the Notch ligand Delta-like 1 (Dll1) is required to maintain quiescent NSCs in the adult mouse subventricular zone. Dll1 protein is induced in activated NSCs and segregates to one daughter cell during mitosis. Dll1-expressing cells reside in close proximity to quiescent NSCs, suggesting a feedback signal for NSC maintenance by their sister cells and progeny. Our data suggest a model in which NSCs produce their own niche cells for their maintenance through asymmetric Dll1 inheritance at mitosis.

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Dll1 is expressed in activated NSCs and transit-amplifying cells in the adult mouse SVZ.(a) Immunofluorescence staining of Dll1 and the indicated markers in the adult SVZ. Arrowheads indicate cells positive for both Dll1 and the corresponding marker. Scale bar, 10 μm. (b) Detection of activated NSCs (GFAP+EGFR+ cells) in the adult SVZ by immunofluorescence staining with antibodies to Dll1, GFAP and EGFR. Arrows indicate a Dll1+EGFR+GFAP+ cell, and arrowheads indicate overlap between EGFR and GFAP staining in a process. The boxed region in the right panel is shown at higher magnification in the inset. Scale bar, 10 μm. LV, lateral ventricle. Broken lines indicate the ventricular surface.
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f4: Dll1 is expressed in activated NSCs and transit-amplifying cells in the adult mouse SVZ.(a) Immunofluorescence staining of Dll1 and the indicated markers in the adult SVZ. Arrowheads indicate cells positive for both Dll1 and the corresponding marker. Scale bar, 10 μm. (b) Detection of activated NSCs (GFAP+EGFR+ cells) in the adult SVZ by immunofluorescence staining with antibodies to Dll1, GFAP and EGFR. Arrows indicate a Dll1+EGFR+GFAP+ cell, and arrowheads indicate overlap between EGFR and GFAP staining in a process. The boxed region in the right panel is shown at higher magnification in the inset. Scale bar, 10 μm. LV, lateral ventricle. Broken lines indicate the ventricular surface.

Mentions: Given an essential role of Dll1 in the maintenance of quiescent NSCs, Dll1-expressing cells would be expected to serve as a niche that maintains this population. Different patterns of Dll1 expression in the adult SVZ have previously been described233234. Using the anti-Dll1 antibody whose specificity was validated as mentioned above, we found that most Dll1+ cells in the SVZ of adult wild-type mice were positive for EGFR (88.8±3.8%) (total counted cells=219, n=3 brains), the transit-amplifying cell marker Ascl1 (78.7±7.3%) (total counted cells=143, n=3 brains) or the cycling cell marker Ki67 (81.0±5.3%) (total counted cells=184, n=3 brains) and were negative for the ependymal cell marker S100β (0%) (total counted cells=184, n=3 brains) or TuJ1 (7.8±3.6%) (total counted cells=145, n=3 brains) (Fig. 4a). Furthermore, 14.4±3.2% of Dll1-expressing cells were positive for both GFAP and EGFR (total counted cells=219, n=3 brains), and most (76.9±8.0%) activated NSCs (GFAP+EGFR+ cells) were positive for Dll1 (total counted cells=46, n=3 brains) (Fig. 4b). These results suggested that activated NSCs and transit-amplifying cells express Dll1, and that these cells might serve as a niche that maintains quiescent NSCs in the adult SVZ. The size of the quiescent NSC pool in the SVZ might therefore be determined by a feedback signal elicited by the activated progeny of these cells.


Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis.

Kawaguchi D, Furutachi S, Kawai H, Hozumi K, Gotoh Y - Nat Commun (2013)

Dll1 is expressed in activated NSCs and transit-amplifying cells in the adult mouse SVZ.(a) Immunofluorescence staining of Dll1 and the indicated markers in the adult SVZ. Arrowheads indicate cells positive for both Dll1 and the corresponding marker. Scale bar, 10 μm. (b) Detection of activated NSCs (GFAP+EGFR+ cells) in the adult SVZ by immunofluorescence staining with antibodies to Dll1, GFAP and EGFR. Arrows indicate a Dll1+EGFR+GFAP+ cell, and arrowheads indicate overlap between EGFR and GFAP staining in a process. The boxed region in the right panel is shown at higher magnification in the inset. Scale bar, 10 μm. LV, lateral ventricle. Broken lines indicate the ventricular surface.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3675328&req=5

f4: Dll1 is expressed in activated NSCs and transit-amplifying cells in the adult mouse SVZ.(a) Immunofluorescence staining of Dll1 and the indicated markers in the adult SVZ. Arrowheads indicate cells positive for both Dll1 and the corresponding marker. Scale bar, 10 μm. (b) Detection of activated NSCs (GFAP+EGFR+ cells) in the adult SVZ by immunofluorescence staining with antibodies to Dll1, GFAP and EGFR. Arrows indicate a Dll1+EGFR+GFAP+ cell, and arrowheads indicate overlap between EGFR and GFAP staining in a process. The boxed region in the right panel is shown at higher magnification in the inset. Scale bar, 10 μm. LV, lateral ventricle. Broken lines indicate the ventricular surface.
Mentions: Given an essential role of Dll1 in the maintenance of quiescent NSCs, Dll1-expressing cells would be expected to serve as a niche that maintains this population. Different patterns of Dll1 expression in the adult SVZ have previously been described233234. Using the anti-Dll1 antibody whose specificity was validated as mentioned above, we found that most Dll1+ cells in the SVZ of adult wild-type mice were positive for EGFR (88.8±3.8%) (total counted cells=219, n=3 brains), the transit-amplifying cell marker Ascl1 (78.7±7.3%) (total counted cells=143, n=3 brains) or the cycling cell marker Ki67 (81.0±5.3%) (total counted cells=184, n=3 brains) and were negative for the ependymal cell marker S100β (0%) (total counted cells=184, n=3 brains) or TuJ1 (7.8±3.6%) (total counted cells=145, n=3 brains) (Fig. 4a). Furthermore, 14.4±3.2% of Dll1-expressing cells were positive for both GFAP and EGFR (total counted cells=219, n=3 brains), and most (76.9±8.0%) activated NSCs (GFAP+EGFR+ cells) were positive for Dll1 (total counted cells=46, n=3 brains) (Fig. 4b). These results suggested that activated NSCs and transit-amplifying cells express Dll1, and that these cells might serve as a niche that maintains quiescent NSCs in the adult SVZ. The size of the quiescent NSC pool in the SVZ might therefore be determined by a feedback signal elicited by the activated progeny of these cells.

Bottom Line: Dll1 protein is induced in activated NSCs and segregates to one daughter cell during mitosis.Dll1-expressing cells reside in close proximity to quiescent NSCs, suggesting a feedback signal for NSC maintenance by their sister cells and progeny.Our data suggest a model in which NSCs produce their own niche cells for their maintenance through asymmetric Dll1 inheritance at mitosis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.

ABSTRACT
Stem cells often divide asymmetrically to produce one stem cell and one differentiating cell, thus maintaining the stem cell pool. Although neural stem cells (NSCs) in the adult mouse subventricular zone have been suggested to divide asymmetrically, intrinsic cell fate determinants for asymmetric NSC division are largely unknown. Stem cell niches are important for stem cell maintenance, but the niche for the maintenance of adult quiescent NSCs has remained obscure. Here we show that the Notch ligand Delta-like 1 (Dll1) is required to maintain quiescent NSCs in the adult mouse subventricular zone. Dll1 protein is induced in activated NSCs and segregates to one daughter cell during mitosis. Dll1-expressing cells reside in close proximity to quiescent NSCs, suggesting a feedback signal for NSC maintenance by their sister cells and progeny. Our data suggest a model in which NSCs produce their own niche cells for their maintenance through asymmetric Dll1 inheritance at mitosis.

Show MeSH