J. Van-riggelen, A. Yetil, and D. W. Felsher, MYC as a regulator of ribosome biogenesis and 602 protein synthesis, Nat Rev Cancer, vol.10, pp.301-309, 2010.

J. Royet, T. Bouwmeester, and S. M. Cohen, Notchless encodes a novel WD40-repeat-604 containing protein that modulates Notch signaling activity, Embo J, vol.17, pp.7351-605, 1998.

S. Cormier, L. Bras, S. Souilhol, C. Vandormael-pournin, S. Durand et al.,

, The Murine Ortholog of Notchless, a Direct Regulator of the Notch Pathway in 608

, Is Essential for Survival of Inner Cell Mass Cells, Drosophila melanogaster, vol.26, pp.3541-3549, 2006.

E. Gazave, P. Lapébie, G. S. Richards, F. Brunet, A. V. Ereskovsky et al., Origin 611 and evolution of the Notch signalling pathway: an overview from eukaryotic 612 genomes, BMC Evol Biol, vol.9, p.249, 2009.

J. La-cruz-de, E. Sanz-martínez, and M. Remacha, The essential WD-repeat protein Rsa4p is 614 required for rRNA processing and intra-nuclear transport of 60S ribosomal subunits, Nucleic Acids Research, vol.615, pp.5728-5739, 2005.

C. Ulbrich, M. Diepholz, J. Baßler, D. Kressler, B. Pertschy et al.,

, Mechanochemical Removal of Ribosome Biogenesis Factors from Nascent 60S

, Ribosomal Subunits. Cell, vol.138, pp.911-922, 2009.

Y. Matsuo, S. Granneman, M. Thoms, R. Manikas, D. Tollervey et al., Coupled GTPase 620 and remodelling ATPase activities form a checkpoint for ribosome export, Nature, vol.621, pp.112-116, 2014.

C. Barrio-garcia, M. Thoms, D. Flemming, L. Kater, O. Berninghausen et al., 623 Architecture of the Rix1-Rea1 checkpoint machinery during pre-60S-ribosome 624 remodeling, Nat Struct Mol Biol, vol.23, pp.37-44, 2015.

L. Bouteiller, M. Souilhol, C. Cormier, S. Stedman, A. Burlen-defranoux et al., , p.626

S. Pournin, Notchless-dependent ribosome synthesis is required for the 627 maintenance of adult hematopoietic stem cells, Journal of Experimental Medicine, vol.628, pp.2351-2369, 2013.

A. Stedman, S. Beck-cormier, L. Bouteiller, M. Raveux, A. Vandormael-pournin et al., , p.630

S. Coqueran, Ribosome biogenesis dysfunction leads to p53-mediated apoptosis 631 and goblet cell differentiation of mouse intestinal stem/progenitor cells, Cell Death 632 Differ, vol.22, pp.1865-1876, 2015.

M. El, F. Janssen, K. Chang, B. Li, M. Hindie et al., Tissue-specific and 634 inducible Cre-mediated recombination in the gut epithelium, Genesis, vol.39, pp.186-635, 2004.

J. Guo, S. Longshore, R. Nair, and B. W. Warner, Retinoblastoma protein (pRb), but not p107 637 or p130, is required for maintenance of enterocyte quiescence and differentiation in 638 small intestine, J Biol Chem, vol.284, pp.134-140, 2009.

T. Léguillier, S. Vandormael-pournin, J. Artus, M. Houlard, C. Picard et al.,

, Omcg1 is critically required for mitosis in rapidly dividing mouse intestinal 641 progenitors and embryonic stem cells, Biol Open, vol.1, pp.648-657, 2012.

N. L. Bray, H. Pimentel, P. Melsted, and L. Pachter, Near-optimal probabilistic RNA-seq 643 quantification, Nat Biotechnol, vol.34, pp.525-527, 2016.

M. I. Love, W. Huber, and S. Anders, Moderated estimation of fold change and dispersion for 645 RNA-seq data with DESeq2, Genome Biol, vol.15, p.550, 2014.

J. Bezanson, A. Edelman, S. Karpinski, V. B. Shah, and . Julia, A Fresh Approach to Numerical 647 Computing, SIAM Review, vol.59, pp.65-98, 2017.

K. R. Reed, V. S. Meniel, V. Marsh, A. Cole, O. J. Sansom et al., A limited role for p53 in 649 modulating the immediate phenotype of Apc loss in the intestine, BMC Cancer, vol.650, p.162, 2008.

J. Pelletier, G. Thomas, and S. Volarevic, Ribosome biogenesis in cancer: new players and 652 therapeutic avenues, Nat Rev Cancer, vol.4, p.3681, 2017.

A. Bastide and A. David, The ribosome, (slow) beating heart of cancer (stem) cell. 654, Oncogenesis, vol.7, p.34, 2018.

H. Tsoi, K. C. Lam, Y. Dong, X. Zhang, C. K. Lee et al., Pre-45s rRNA promotes colon 656 cancer and is associated with poor survival of CRC patients, vol.657, 2017.

W. J. Faller, T. J. Jackson, J. Knight, R. A. Ridgway, T. Jamieson et al., mTORC1-659 mediated translational elongation limits intestinal tumour initiation and growth, Nature, vol.517, pp.497-500, 2015.

P. M. Bruno, Y. Liu, G. Y. Park, J. Murai, C. E. Koch et al., A subset of platinum-662 containing chemotherapeutic agents kills cells by inducing ribosome biogenesis 663 stress, Nature Medicine, vol.23, pp.461-471, 2017.

A. M. Cole, K. B. Myant, K. R. Reed, R. A. Ridgway, D. Athineos et al., Cyclin 665 D2-Cyclin-Dependent Kinase 4/6 Is Required for Efficient Proliferation and 666 Tumorigenesis following Apc Loss, Cancer Research, vol.70, pp.8149-8158, 2010.

G. H. Ashton, J. P. Morton, K. B. Myant, T. J. Phesse, R. A. Ridgway et al., Focal 668 adhesion kinase is required for intestinal regeneration and tumorigenesis 669 downstream of Wnt/c-Myc signaling, Dev Cell, vol.19, pp.259-269, 2010.

A. Z. Holik, M. Young, J. Krzystyniak, G. T. Williams, D. Metzger et al., Brg1 671 loss attenuates aberrant wnt-signalling and prevents wnt-dependent 672 tumourigenesis in the murine small intestine, PLoS Genet, vol.10, p.1004453, 2014.

T. Eom and R. S. Jope, GSK3 beta N-terminus binding to p53 promotes its acetylation, Mol 674 Cancer, vol.8, p.14, 2009.

R. Kulikov, K. A. Boehme, and C. Blattner, Glycogen synthase kinase 3-dependent 676 phosphorylation of Mdm2 regulates p53 abundance, Mol Cell Biol, vol.25, pp.7170-677, 2005.

A. S. Pfister, M. Keil, and M. Kühl, The Wnt Target Protein Peter Pan Defines a Novel p53-679 independent Nucleolar Stress-Response Pathway, Journal of Biological Chemistry, vol.680, pp.10905-10918, 2015.

M. L. Kraushar, B. Viljetic, H. Wijeratne, K. Thompson, X. Jiao et al., Thalamic 682 WNT3 Secretion Spatiotemporally Regulates the Neocortical Ribosome Signature 683 and mRNA Translation to Specify Neocortical Cell Subtypes, Journal of Neuroscience, vol.684, pp.10911-10926, 2015.

N. R. Genuth and M. Barna, Heterogeneity and specialized functions of translation 686 machinery: from genes to organisms, Nat Rev Genet, vol.13, p.1, 2018.

A. M. Cole, R. A. Ridgway, S. E. Derkits, L. Parry, N. Barker et al., p21 loss blocks 688 senescence following Apc loss and provokes tumourigenesis in the renal but not the 689 intestinal epithelium, EMBO Mol Med, vol.2, pp.472-486, 2010.

T. Teng, C. A. Mercer, P. Hexley, G. Thomas, and S. Fumagalli, Loss of tumor suppressor 691

, RPL5/RPL11 does not induce cell cycle arrest but impedes proliferation due to 692 reduced ribosome content and translation capacity, Mol Cell Biol, vol.33, pp.4660-693, 2013.

T. Sato, R. G. Vries, H. J. Snippert, M. Van-de-wetering, N. Barker et al., Single 695 Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche, Nature, vol.459, pp.262-265, 2009.

N. Bohin, E. A. Carlson, and L. C. Samuelson, Genome Toxicity and Impaired Stem Cell 698 Function after Conditional Activation of CreERT2 in the Intestine, Stem Cell Reports, vol.699, pp.1337-1346, 2018.

, Hematoxylin (blue) on intestinal epithelium sections from Control, p.737

, Apc cKO ; Nle cKO intestines at day 3 pi harvested 2 hours or 48 hours after BrdU injection

, Dotted black bars indicate the 739 range of proliferative cell migration within 48 hours. Scale bars, vol.50, p.740

, Caspase 3 immunostaining (brown) counterstained with Hematoxylin (blue) on intestinal 741 epithelium sections from Control, Apc cKO and Apc cKO

, Arrowheads indicate Caspase 3-positive cells. Scale bars, 50 ?m, p.2

, immunostaining (brown) counterstained with Hematoxylin (blue) on intestinal 744 epithelium sections from Control, Apc cKO and Apc cKO

, Hematoxylin (blue) on intestinal epithelium sections from Control, p.747

, Nle cKO intestines at day 2 pi. Scale bars, 50 ?m. (E) Histogram showing the mean 748 number (+/-SEM) of Caspase 3 positive cells per crypt in Control, p.749

, Nle cKO intestines at day 2 pi. 30 transverse crypts were scored per mouse, n?3 for 750 each genotype. *, P<0.05 Mann-Whitney Wilcoxon test, p.751

, Apc cKO and Apc cKO ; Nle cKO intestinal crypt extracts at day 2 pi. Graphs 752 represent the mean fold changes ±, S.E.M. for differentiation markers Mucin, vol.2, p.753

A. Chromogranin and . Chromoa, n ? 3 for each genotype. *, p<0.05 **, p<0.01 according to 754

. Mann-whitney, Wilcoxon test

, Figure 4 Nle loss-of-function leads to ribosome biogenesis defects and p53 757 stabilization in the Apc-deficient epithelium. (A) Simplified diagram illustrating the 758 main steps of ribosome biogenesis in eukaryotic cells. Blue arrows represent the primers 759 used to measure the levels of ribosomal RNAs by RT-qPCR

, its1 (red) and its2 (green) sequences from precursors of the small and large ribosomal 761

, subunits, respectively, are indicated. (B) RT-qPCR performed on total RNA from Control, p.762

A. Cko and A. Cko, Nle cKO intestinal crypt extracts at day 2 pi, Graphs represent the mean 763 fold changes ± S.E.M. for the different amplicons. n = 4 for each genotype. *, p<0.05 **, p.764

*. , 001 according to Student's t-test. (C) FISH for its1 (red) or its2 (yellow), p.765

, counterstained with Hoechst (blue) on intestinal epithelium sections from Control, Apc cKO, p.766

A. Cko,