RAB11A and RAB11B control mitotic spindle function in intestinal epithelial progenitor cells
- PMID: 37424454
- PMCID: PMC10481667
- DOI: 10.15252/embr.202256240
RAB11A and RAB11B control mitotic spindle function in intestinal epithelial progenitor cells
Abstract
RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues.
Keywords: KIF11; RAB11A; RAB11B; mitosis; spindle.
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
Figures
- A
Survival graphs of newborn pups from breeding of Rab11a Fl/+; Rab11b +/−; Villin‐Cre and Rab11a Fl/+; Rab11b +/− (or Rab11a Fl/+; Rab11b −/−) mice. The total number of pups for each genotype was labeled next to the corresponding curve. The graph represents over six independent litters from three different mating pairs.
- B
Western blots for Rab11a and Rab11b using small intestinal lysates prepared from adult wild‐type (WT, lane 1), Rab11a Fl/Fl ; Villin‐CreER (aKO, lane 2) 2 days after tamoxifen treatment, Rab11b −/− (bKO, lane 3), and Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER (DKO) mice 1 day (lane 4), 2 days (lane 5), and 3 days (lane 6) after tamoxifen treatment. All mice were given a single tamoxifen injection. β‐actin was used as loading control. Results represent more than three independent experiments.
- C
H. & E. staining of adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice, before and after tamoxifen injection. Images represent jejunum tissues collected 1, 2, and 3 days following tamoxifen injection. Experiments were repeated over five times using independent litters (n > 10). Scale bars, 50 μm.
- D
Alkaline phosphatase (AP) staining was performed on intestinal tissue sections of adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice that were treated with corn oil or with tamoxifen. Results represent at least three independent experiments. Scale bars, 50 μm.
- E
Quantification of AP staining in mice of various genotypes. The AP fluorescent signal abundance per crypt‐villus axis was quantified by ImageJ. Data represent 5–6 different microscopic fields taken from three mice per condition.
- F
Alcian blue staining was performed on adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before or 1–3 days after tamoxifen injection. Results represent at least three independent experiments. Scale bars, 100 μm.
- G
Quantification of the number of Alcian blue‐positive cells per crypt‐villus axis in mice of various genotypes. Data represent average values of approximately 10–15 different microscopic fields taken from three mice per condition.
- H
Immunofluorescent staining for lysozyme and E‐Cad was performed on adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before and after tamoxifen injection. Experiments represent three independent replicates. Scale bars, 50 μm.
- I
Quantification of lysozyme fluorescent signal abundance per crypt in mice of various genotypes. Data represent approximately 10–15 different microscopic fields taken from three mice per condition.
- J
Bulk RNA sequencing was performed on WT, aKO, bKO, and DKO mouse jejunum tissues (n = 3 each group) 2 days after tamoxifen injection. The resulting transcriptomes were analyzed by principle coordinate analysis.
- K
Gene set enrichment analysis (GSEA) was performed for villus epithelial differentiation transcriptome to compare WT and DKO mice. This differentiation gene set was significantly reduced in DKO. P‐value < 0.001.
- A
Schematic diagram shows the localization of two guiding RNAs (sgRNA) that were used in CRISPR‐CAS9‐mediated genome editing at Rab11b locus. Three primers that were used to distinguish wild‐type and modified Rab11b alleles are displayed as arrows.
- B
Genomic sequences of wild‐type, Rab11bΔ2, and Rab11bΔ2‐4 alleles. Two independently modified Rab11b alleles (Rab11bΔ2 and Rab11bΔ2‐4) were established and sequence‐validated.
- C
Predicted amino acid sequences of wild‐type, Rab11bΔ2, and Rab11bΔ2‐4 alleles. Both Rab11bΔ2 and Rab11b Rab11bΔ2, and Rab11bΔ2‐4 Δ2‐4 have deletion in the entire GTPase domain of Rab11b.
- A
Body weight changes (% of pretreatment weight) in adult mice of various genotype after tamoxifen injection. Note, within 3 days following tamoxifen injection, all Rab11aFl/Fl; Rab11b−/−; Villin‐CreER (DKO) mice died.
- B
Wide field of intestinal histology of Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before and after TAM injection shown in Fig 1C. Crypt regions are boxed and shown in high magnifications.
- C
Immunofluorescent staining for Villin and E‐Cad was performed on adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before and 1, 2, and 3 days after tamoxifen injection.
- D
Representative Ki67 immunohistochemistry on adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before and 1, 2, and 3 days after tamoxifen injection.
- A
GSEA analysis shows increased epithelial cell proliferation gene sets in DKO mice.
- B
Immunohistochemistry for Ki67 staining was performed on intestinal sections of adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before and after tamoxifen injection. Experiments represent three independent replicates. Scale bars, 50 μm.
- C
Quantification of ratio of Ki67+ cells over total epithelial cells per crypt‐villus axis in DKO mice before and after tamoxifen treatment. Data represent approximately 10–15 different microscopic fields taken from three mice per condition.
- D
Immunofluorescent staining for pHH3 and E‐Cad was performed on intestinal sections of adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before and after tamoxifen injection. Experiments represent three independent replicates. Scale bars, 50 μm.
- E
Quantification of ratio of pHH3+ cells over total IECs per crypt in DKO mice before and after tamoxifen treatment. Data represent approximately 10–15 different microscopic fields taken from three mice per condition.
- F
Heat maps of intestinal stem cell signature genes of mice of various genotypes.
- G
Representative western blots for Olfm4 and pHH3 in intestinal tissue lysates of DKO mice before and after tamoxifen injection.
- H
Immunohistochemistry for Olfm4 was performed on intestinal sections of adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before and after tamoxifen injection. Experiments represent three independent replicates. Scale bars, 50 μm.
- I
Quantification of Olfm4+ cell number per crypt in DKO mice before and after tamoxifen treatment. Data represent approximately 10–15 different microscopic fields taken from three mice per condition.
- J
Immunofluorescent staining for Sox9 and E‐Cad in DKO mice before and after tamoxifen treatment. Scale bars, 50 μm.
- K
Quantification of Sox9+ cell number per crypt in DKO mice before and after tamoxifen treatment. Data represent approximately 10–15 different microscopic fields taken from three mice per condition.
- L
Immunohistochemistry for c‐Myc was performed on intestinal sections of adult Rab11a Fl/Fl ; Rab11b −/−; Villin‐CreER mice before and after tamoxifen injection. Experiments represent three independent replicates. Scale bars, 50 μm.
- M
Quantification of c‐Myc+ cell number per crypt‐villus axis in DKO mice before and after tamoxifen treatment. Data represent approximately 10–15 different microscopic fields taken from three mice per condition.
- A, B
Jejunum epithelial cells were prepared as single‐cell suspension from WT and DKO mice 2 days after tamoxifen injection, stained with propidium iodide, and analyzed for cell cycle distribution by flow cytometry. Pie graphs represent five mice for each genotype in two independent experiments. There was a S‐phase (P < 0.001) and G2/M phase arrest (P < 0.05) in DKO, compared with WT.
- C
A schematic diagram shows the sequential CIdU and IdU pulse‐chase labeling experiments. WT and DKO mice were injected with tamoxifen, first injected by CIdU (green) to label S‐phase WT and DKO cells; the mice were sacrificed in pairs 1–1.5 days later, with each mouse receiving an IdU (red) injection 3 h before sacrifice to label new dividing cells.
- D
Immunofluorescent staining for CIdU (green) and IdU (red) in WT and DKO mouse small intestines. An upwards movement of CIdU cells was present in WT but not in DKO mice. White arrows point to CIdU+ DKO epithelial cells that were shedding off the villus surface. Scale bars, 50 μm.
- E
Quantification of CIdU+/IdU+ cell number per crypt‐villus axis. Data represent 10–15 different microscopic fields taken from three mice per condition.
- F
High magnification images were taken from CIdU/IdU labeled WT and DKO mouse crypt regions to visualize double‐positive cells. White arrows point to shedding CIdU cells. Scale bars, 50 μm.
- G, H
Quantification of IdU+ cells, and shedding CIdU+ cells per crypt‐villus axis in WT and DKO mice. Data represent 10–15 different microscopic fields taken from three mice per condition.
- A
HEK293T cells were transfected with 3 × Flag‐Rab11a and 3 × Flag‐Rab11b, respectively. Immunoprecipitation was performed by using anti‐Flag antibody, and the precipitates were resolved on SDS–PAGE, stained by ruby red, and subjected to untargeted proteomic analysis.
- B
Heat maps based on unique peptides of protein targets identified by mass spectrometry in 3 × Flag‐Rab11a (952 proteins) and 3 × Flag‐Rab11b (1,470 proteins) immunoprecipitates. The data were transformed by natural log. Targets with high numbers of unique peptide counts, KIF11, MYH10, and Rab11FlP1, are denoted.
- C
Venn diagram shows that 885 protein targets were shared by Rab11a and Rab11b. Note, the majority came down in complexes and may not be direct interactors due to the methods used.
- D
Gene Ontology analysis of Rab11a and Rab11b common targets revealed enriched functional networks in DNA replication (P = 1.6 × 10−7), cell cycle (P = 1.7 × 10−5), cell division (P = 3 × 10−4), and mitosis (P = 1.2 × 10−3).
- E
The top 10 shared targets ranked by number of spectrum counts (SC) from high to low. Unique peptide (UP) numbers are also provided for each target.
- F
Co‐IP assays were performed in HEK293T cells to validate the association between 3 × Flag‐Rab11a, 3 × Flag‐Rab11b and endogenous KIF11. Lane 1: input lysate; lane 2: flow‐through after co‐IP; lane 3–5: 3 washes; lane 6: on beads; and lane 7: immunoprecipitation elutes. Cells transfected with 3 × Flag empty vector were used as a negative control. Experiments repeated over six times.
- G
Cells were transfected with mCherry‐tagged WT, Rab11‐S25N, and Rab11‐S20V, fixed and stained for endogenous KIF11 (gray) and pericentrin (green). The mCherry signal (red) represents direct fluorescent signal visualized under confocal microscope. Arrows denote position of spindle poles defined by pericentrin. Images represent three independent experiments. Scale bars, 10 μm.
- H
Quantification of the percentage of bipolar, monopolar, or multipolar (three or more) spindles observed in mitotic cells identified from each microscopic field. Data represent 10–20 independent fields per condition from three experiments.
- I
Immunofluorescent staining for KIf11 (green) and E‐Cad (gray) in WT and DKO mouse intestines. Yellow arrows point to Kif11+ spindles. Images represent at least 10 images per mouse and five mice for each genotype. Scale bars, 50 μm.
- J
WT and DKO mice were injected with IdU 3 h before sacrifice to label new dividing cells. Immunofluorescent staining for KIf11 (green), E‐Cad (gray), and IdU (red) was performed. Yellow arrows point to abnormal Kif11 localization in DKO cells. Scale bars, 50 μm.
- K
Based on Kif11 spindle morphology, quantification of the percentage of bipolar and abnormal (monopolar, tilted bipolar) spindles was done on WT and DKO intestinal sections. Results were quantified from mitotic cells of 20 independent fields of 5–6 mice for each genotype.
- L, M
Immunofluorescent staining for KIf11 (red) and spindle pole markers γ‐tubulin or pericentrin (green) in WT and DKO mouse intestines. Images represent three mice for each genotype. White arrows point to spindle pole. Scale bars, 20 μm, 10 μm.
- A
Mass spectrometry proteomic analysis of Rab11a and Rab11b immunoprecipitates revealed KIF11, which showed 37 exclusive peptides (yellow‐highlighted) out of the 58 total spectrum from Rab11a precipitates; 20 exclusive peptides out of the 21 total spectrum from Rab11b precipitates.
- B
Representative images of HEK293T cells transfected with mCherry‐tagged Rab11a‐S25N showing tripolar or multipolar spindles. Cells were stained for Kif11 (gray) and pericentrin (green). Arrows point to spindle poles. mCherry signal is direct fluorescence.
- C
Z‐stack and 3D view of HEK293T cells transfected with mCherry‐tagged WT Rab11a, S25N, and S20V. Cells were stained for Kif11 (red) and pericentrin (green). mCherry (gray) signal is direct fluorescence. Arrows point to spindle poles.
- A
Live cell imaging was performed on dividing HEK293T cells that were labeled with SiR‐tubulin (green) and were transiently transfected with mCherry‐tagged wild‐type Rab11a, Rab11a (S25N), and Rab11a (S20V). Arrows point to spindle poles. Numbers indicate seconds of each event during live cell imaging.
- B
Percentages of mitotic cells within transfected populations were similar across different transfection conditions.
- C–E
In interphase cells, lines were drawn across the center of microtubule‐organizing center for the analysis of Rab11a and tubulin localization.
- F–H
Histograms of line‐scan analysis by ImageJ show the fluorescent intensity of mCherry Rab11a (red) and tubulin (gray) across the microtubule‐organizing centers of in interphase cells transfected with different Rab11a plasmids. The fluorescent signals were converted to gray scale and quantified by ImageJ. Data represent 10–20 independent fields per condition.
- A
Immunofluorescent staining for Kif11 (green) and E‐Cad (gray) was performed on TAM‐treated WT and DKO mice. Representative bipolar spindles in WT and various abnormal spindles in DKO were pointed by arrows.
- B
Mice were labeled with IdU for 3 h before sacrifice to label new dividing cells. Immunofluorescent staining for Kif11 (green) and IdU (red) was performed on TAM‐treated WT and DKO mice. Representative bipolar spindles in WT and various abnormal spindles in DKO were pointed by arrows.
- A
A schematic diagram of full length and three truncated KIF11 that represent the motor, the stalk, and the tail domains. All fragments were tagged by a V5 epitope. The corresponding amino acids of each fragment are labeled on the left.
- B, C
HEK293T cells were transiently transfected with 3 × Flag‐Rab11a (or 3 × Flag‐Rab11b) and V5‐tagged KIF11 truncates. Lysates were immunoprecipitated by anti‐Flag antibody and probed by an anti‐V5 antibody to assess intracellular associations. Cells transfected by V5 empty vector were used as a negative control.
- D
HEK293T cells were transiently transfected with V5‐tagged KIF11 truncates or empty vector, fixed, and stained for KIF11. Percentage of bipolar, monopolar, and multipolar spindles were scored from total mitotic cells identified from each field. Independent fields of three biological replicates per condition were analyzed and represented as stacking bar graphs.
- E
Immunofluorescent staining for α‐Tubulin and KIF11 was performed on HEK293T cells treated with 0.1% DMSO (as a control), 50 μM monastrol, 2.5 μM STLC, or 100 nM ispinesib. Experiments were done three times. Scale bars, 10 μm.
- F
Co‐IP assays for 3 × Flag‐Rab11a and endogenous KIF11 were performed using HEK293T cells treated with various KIF11 inhibitors. Cells treated with DMSO were used as a control. Anti‐Flag precipitates were probed by anti‐KIF11 and anti‐Flag antibodies.
- G
Quantification of co‐immunoprecipitated KIF11 was normalized to input KIF11 from cells treated by different inhibitors. DMSO data were quantified for five experimental replicates, and all other treatments were quantified for four experimental replicates.
- H
HEK293T cells were transiently transfected with 3 × Flag‐Rab11a and treated with nocodazole (100 ng/ml) or vehicle overnight, and lysates were used for Flag immunoprecipitation followed by immunoblot for KIF11. Quantification of co‐immunoprecipitated KIF11 was normalized to input KIF11 from control (n = 6) and nocodazole‐treated (n = 9) cells.
- I
Endogenous KIF11 was immunoprecipitated from WT and RAB11‐knockdown (KD) Caco2 cells. The precipitates were resolved on SDS–PAGE, stained by ruby red, and subjected to an untargeted proteomic analysis.
- J
Venn diagram showing that targets (244) in KIF11 precipitates of WT cells were absent from RAB11‐KD cells.
- K
STRING analysis of KIF11 co‐precipitated targets involved in DNA replication, mitosis, and cell cycle regulation.
- L
KIF11 co‐IP analysis was performed using WT and RAB11‐KD CaCo2 cell lysates. The immunoprecipitates were probed for CLIP1, ZW10, CCAR1, USO1, and CCNB1. Experiments represent 2–4 replicates for each target.
- M
Quantification of KIF11‐CLIP1 co‐immunoprecipitates from WT and RAB11‐KD CaCo2 cells in three independent experiments.
- N
Immunofluorescent staining for endogenous Clip1 (red) and Kif11 (green) in WT and Rab11 DKO mouse intestinal epithelial tissues. n = 4–5 mice for each genotype. White arrows point to Kif11+ spindles. Scale bars, 20 μm.
- O
Pearson's correlation of CLIP1 and KIF11 at mitotic spindles of WT and Rab11 DKO IECs. Results were analyzed from 21 and 13 mitotic cells in 5–10 independent microscopic images of WT and DKO tissues, respectively.
- A
Enteroids were grown from mice of different genotypes. Images were taken before and after addition of 4‐OHT that induces Rab11a deletion. Twenty–thirty images were taken daily from independent fields of cultures. Each genotype had replicates, and experiments were done twice. Scale bars, 500 μm.
- B
Propidium iodide (PI) staining of WT, BKO, and DKO enteroids 3 days after 4‐OHT treatment ex vivo. Note DKO enteroids had increased PI staining along the epithelial edge. Vehicle‐treated DKO enteroids were used as controls. Scale bars, 200 μm.
- C
PI‐stained areas were normalized to total enteroid area for each enteroid of different genotypes.
- D, E
Histology sections of harvested enteroids of different genotypes were stained by H. & E. Enteroids showing impaired epithelial lining were scored from independent fields (n = 8, 10 and 7 for WT, BKO, and DKO, respectively) of biological replicates. Scale bars, 100 μm.
- F, G
Immunofluorescent staining for Kif11 (red) and E‐cad (green) was performed on enteroids of various genotypes, all of which were treated with 4‐OHT. Same experiments were done for DKO enteroids treated with vehicle or 4‐OHT. White arrows point to Kif11+ spindles. Scale bars, 20 μm.
- H
Normal bipolar Kif11 spindles were counted per enteroid of vehicle (n = 10) or 4‐OHT treated DKO (n = 10) enteroids from biological replicates. Images were analyzed from two independent experiments.
- I, J
Numbers of pHH3+ or Lyz1+ cells were counted per enteroid of vehicle (n = 11 for pHH3; n = 8 for Lyz1) or 4‐OHT treated DKO (n = 9 for both pHH3 and Lyz1) enteroids from biological replicates.
- K, L
Representative confocal fluorescent images of pHH3 (red) or Lyz1 (red) stained with E‐Cad (green) from vehicle or 4‐OHT treated DKO enteroids. Scale bars, 50 μm.
- A
Immunohistochemistry for cleaved caspase 3 (CC3) was performed on TAM‐treated enteroids of different genotypes. Black arrows point to CC3+ cells at the epithelial lining of DKO enteroids. Scale bars, 50 μm.
- B
Quantification of number of CC3+ cells within epithelial lining of enteroids of different genotypes and treatments. N = 9 for WT, BKO, BKO + TAM, and DKO; n = 7 for WT + TAM; n = 11 for DKO + TAM of biological replicates.
- C
Heat map of apoptotic genes in WT and Rab11 DKO intestinal transcriptomes (n = 3 for each genotype).
- D
GSEA analysis shows significantly enriched apoptotic gene set in Rab11 DKO intestinal epithelia compared with WT littermates. P < 0.001.
- E–H
Representative apoptotic genes, Anxa1, Anxa5, Bcl2l1, Bcl10, which were highly elevated in DKO intestines. n = 3 mice for each genotype.
- I
Immunofluorescent staining for CC3 (green) was performed on WT and Rab11 DKO intestinal epithelial tissues before and after tamoxifen treatment. Scale bars, 50 μm.
- J
Quantification of CC3‐positive cells per crypt‐villus axis in WT and Rab11 DKO intestines. Results were obtained from 10 to 15 independent microscopic images taken from 4 to 5 mice for each genotype.
- K
Heat map of TNFA‐NFκB pathway genes in WT and Rab11 DKO intestinal transcriptomes (n = 3 for each genotype).
- L
Tnf transcripts were highly elevated in DKO intestines. n = 3 mice for each genotype.
- M
GSEA analysis shows significantly enriched TNFA‐NFκB pathway gene set in Rab11 DKO compared with WT littermates.
- N
Immunohistochemistry for NFκB was performed on WT and Rab11 DKO intestinal tissues.
- O
Quantification of ratio of nuclear NFκB+ cell number over total IECs per crypt‐villus axis. Data were analyzed from 10 to 15 independent microscopic fields. n = 4–5 mice for each genotype.
- P
Immunofluorescent staining for p53 (green) and E‐cad (red) in WT and Rab11 DKO intestinal tissues. Scale bars, 50 μm, 20 μm.
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