Notchless-dependent ribosome synthesis is required for the maintenance of adult hematopoietic stem cells.
Blood cell production relies on the coordinated activities of hematopoietic stem cells (HSCs) and multipotent and lineage-restricted progenitors. Here, we identify Notchless (Nle) as a critical factor for HSC maintenance under both homeostatic and cytopenic conditions. Nle deficiency leads to a rapid and drastic exhaustion of HSCs and immature progenitors and failure to maintain quiescence in HSCs. In contrast, Nle is dispensable for cycling-restricted progenitors and differentiated cells. In yeast, Nle/Rsa4 is essential for ribosome biogenesis, and we show that its role in pre-60S subunit maturation has been conserved in the mouse. Despite its implication in this basal cellular process, Nle deletion affects ribosome biogenesis only in HSCs and immature progenitors. Ribosome biogenesis defects are accompanied by p53 activation, which causes their rapid exhaustion. Collectively, our findings establish an essential role for Nle in HSC and immature progenitor functions and uncover previously unsuspected differences in ribosome biogenesis that distinguish stem cells from restricted progenitor populations.
Institut Pasteur, Unité de Génétique Fonctionnelle de la Souris, Département de Biologie du Développement et Cellules Souches, F-75015 Paris, France.
Marie
M
Le Bouteiller
Céline
C
Souilhol
Sarah
S
Beck-Cormier
Aline
A
Stedman
Odile
O
Burlen-Defranoux
Sandrine
S
Vandormael-Pournin
Florence
F
Bernex
Ana
A
Cumano
Michel
M
Cohen-Tannoudji
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D001853:Bone Marrow / Q000378:metabolism; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology; D012335:RNA, Ribosomal / Q000378:metabolism; D054657:Ribosome Subunits / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D008565:Membrane Proteins; D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53; C510343:notchless protein, mouse