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miR-144/451 represses the LKB1/AMPK/mTOR pathway to promote red cell precursor survival during recovery from acute anemia

Fang, Xiao, Shen, Feiyang, Lechauve, Christophe, Xu, Peng, Zhao, Guowei, Itkow, Jacobi, Wu, Fan, Hou, Yaying, Wu, Xiaohui, Yu, Lingling, Xiu, Huiqing, Wang, Mengli, Zhang, Ruiling, Wang, Fangfang, Zhang, Yanqing, Wang, Daxin, Weiss, Mitchell J., Yu, Duonan·2018·Haematologica
DOI 10.3324/haematol.2017.177394PMC PMC5830375
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Figure 1. Increased apoptosis of miR-144/451−/− erythroblasts during erythropoietic stress. (A) miR-144/451−/− progenitor cells were isolated from E14.5 fetal liver (FL) erythroblasts and grown in culture in expansion medium or maturation medium. (B) Cell proliferation rates of FL erythroid blasts in expansion medium for 24 and 48 hours (h). n=3 FLs. **P<0.01 (t-test). Experiments were repeated 3 times. (C) Flow cytometry-based analysis of apoptosis using Annexin V. (D) Quantitative analysis of the flow cytometry data from (C). Data from 3 independent experiments. **P<0.01 (t-test). (E) Quantitative PCR analysis of miR-451 expression in FL progenitors grown in expansion medium for different lengths of time. Progenitor cells from miR-144/451−/− FLs, mouse B-lymphoma cell line 38B9, and normal B lymphocytes sorted from mouse bone marrow were used as negative controls. Note: the high miR-451 expression in the 0-h culture suggests the erythroid identity of the progenitors, whereas the lack of a significant increase in miR-451 after 48 h in culture suggests that there is no further differentiation of erythroid progenitors grown in culture. (F) FL progenitors grown in expansion medium for 48 h. Cells were cytospun onto slides and stained with May-Grunwald-Giemsa. (G) Cell proliferation rates of FL erythroid cells in maturation medium for 24 and 48 h. N=3. **P<0.01 (t-test). (H) Percentage of apoptotic cells in maturation medium based on flow cytometric analysis. Data represent 3 independent experiments. **P<0.01 (t-test). (I) Cell numbers in whole E14.5 FLs without in vitro expansion. WT n=10, KO n=11. *P<0.05 (t-test). (J) Percentage of apoptotic cells in different regions gated by CD71/Ter119 staining and FSC intensity. WT n=7, KO n=6. *P<0.05 (t-test).
Figure 1. Increased apoptosis of miR-144/451−/− erythroblasts during erythropoietic stress. (A) miR-144/451−/− progenitor cells were isolated from E14.5 fetal liver (FL) erythroblasts and grown in culture in expansion medium or maturation medium. (B) Cell proliferation rates of FL erythroid blasts in expansion medium for 24 and 48 hours (h). n=3 FLs. **P<0.01 (t-test). Experiments were repeated 3 times. (C) Flow cytometry-based analysis of apoptosis using Annexin V. (D) Quantitative analysis of the flow cytometry data from (C). Data from 3 independent experiments. **P<0.01 (t-test). (E) Quantitative PCR analysis of miR-451 expression in FL progenitors grown in expansion medium for different lengths of time. Progenitor cells from miR-144/451−/− FLs, mouse B-lymphoma cell line 38B9, and normal B lymphocytes sorted from mouse bone marrow were used as negative controls. Note: the high miR-451 expression in the 0-h culture suggests the erythroid identity of the progenitors, whereas the lack of a significant increase in miR-451 after 48 h in culture suggests that there is no further differentiation of erythroid progenitors grown in culture. (F) FL progenitors grown in expansion medium for 48 h. Cells were cytospun onto slides and stained with May-Grunwald-Giemsa. (G) Cell proliferation rates of FL erythroid cells in maturation medium for 24 and 48 h. N=3. **P<0.01 (t-test). (H) Percentage of apoptotic cells in maturation medium based on flow cytometric analysis. Data represent 3 independent experiments. **P<0.01 (t-test). (I) Cell numbers in whole E14.5 FLs without in vitro expansion. WT n=10, KO n=11. *P<0.05 (t-test). (J) Percentage of apoptotic cells in different regions gated by CD71/Ter119 staining and FSC intensity. WT n=7, KO n=6. *P<0.05 (t-test).CC BY-NC · PubMed Central
Figure 2. Apoptotic erythroblasts in miR-144/451−/− bone marrow increase after administration of 5-fluorouracil (5-FU) in adult mice. (A) Survival rates after 5-FU treatment for n=38 (wild-type, WT) and n=36 (miR-144/451−/−, KO) mice. (B) Increased hemolysis of miR-144/451−/− erythrocytes after exposure to 5-FU, as determined by serial hematocrit measurement. N=12 miR-144/451−/− and n=12 WT mice were used. *P<0.05; **P<0.01 (t-test). (C) Flow cytometric analysis of Ter119+CD71+ reticulocytes in circulating blood after 5-FU treatment. N=5 mice of each genotype were used. **P<0.01 (t-test). Note: for the first eight days there were relatively more reticulocytes in miR-144/451−/− blood as compared to WT blood, but significantly fewer during days 8 to 12. The number of reticulocytes in miR-144/451−/− blood dramatically increased around day 14, and much higher levels were sustained than in WT animals. (D) Flow cytometric analysis of Ter119+CD71+ erythroid cells in bone marrow after 5-FU administration for 7–11 days. Note: the appearance of Ter119+CD71+ erythroid cells in bone marrow was delayed relative to that in WT mice, indicating a maturation arrest and/or sustained apoptosis of erythroid cells in miR-144/451−/− mice. (E) Quantitated analysis of Ter119+CD71+ erythroid cells in bone marrow after 5-FU administration for 7–11 days. There were n=5 mice of each genotype at each time point. **P<0.01 (t-test). (F) Flow cytometric analysis of nucleated cell numbers in bone marrow after 5-FU administration. All cells shown in the windows were Ter119+. Gated regions represent nucleated erythroblasts (Hoechst+FSChigh). (G) Quantitative analysis of flow cytometry data from (F). There were n=5 mice of each genotype at each time point. **P<0.01 (t-test). Note: there were far fewer nucleated erythroid cells in miR-144/451−/− bone marrow during days 9 to 11, indicating a maturation arrest and/or sustained apoptosis. (H) Flow cytometric analysis of early apoptosis using Annexin V. Ter119+/Hoechst+ cells are nucleated erythroid cells (left). Near-IR cell death marker−/Annexin V+ cells are early apoptotic cells (right). (I) Quantitative analysis of flow cytometry data from (H). We used n=5 mice of each genotype at day 11 after 5-FU treatment. **P<0.01 (t-test).
Figure 2. Apoptotic erythroblasts in miR-144/451−/− bone marrow increase after administration of 5-fluorouracil (5-FU) in adult mice. (A) Survival rates after 5-FU treatment for n=38 (wild-type, WT) and n=36 (miR-144/451−/−, KO) mice. (B) Increased hemolysis of miR-144/451−/− erythrocytes after exposure to 5-FU, as determined by serial hematocrit measurement. N=12 miR-144/451−/− and n=12 WT mice were used. *P<0.05; **P<0.01 (t-test). (C) Flow cytometric analysis of Ter119+CD71+ reticulocytes in circulating blood after 5-FU treatment. N=5 mice of each genotype were used. **P<0.01 (t-test). Note: for the first eight days there were relatively more reticulocytes in miR-144/451−/− blood as compared to WT blood, but significantly fewer during days 8 to 12. The number of reticulocytes in miR-144/451−/− blood dramatically increased around day 14, and much higher levels were sustained than in WT animals. (D) Flow cytometric analysis of Ter119+CD71+ erythroid cells in bone marrow after 5-FU administration for 7–11 days. Note: the appearance of Ter119+CD71+ erythroid cells in bone marrow was delayed relative to that in WT mice, indicating a maturation arrest and/or sustained apoptosis of erythroid cells in miR-144/451−/− mice. (E) Quantitated analysis of Ter119+CD71+ erythroid cells in bone marrow after 5-FU administration for 7–11 days. There were n=5 mice of each genotype at each time point. **P<0.01 (t-test). (F) Flow cytometric analysis of nucleated cell numbers in bone marrow after 5-FU administration. All cells shown in the windows were Ter119+. Gated regions represent nucleated erythroblasts (Hoechst+FSChigh). (G) Quantitative analysis of flow cytometry data from (F). There were n=5 mice of each genotype at each time point. **P<0.01 (t-test). Note: there were far fewer nucleated erythroid cells in miR-144/451−/− bone marrow during days 9 to 11, indicating a maturation arrest and/or sustained apoptosis. (H) Flow cytometric analysis of early apoptosis using Annexin V. Ter119+/Hoechst+ cells are nucleated erythroid cells (left). Near-IR cell death marker−/Annexin V+ cells are early apoptotic cells (right). (I) Quantitative analysis of flow cytometry data from (H). We used n=5 mice of each genotype at day 11 after 5-FU treatment. **P<0.01 (t-test).CC BY-NC · PubMed Central
Figure 3. Apoptosis of miR-144/451−/− bone marrow and spleen erythroblasts is increased under other stress conditions. (A and B) Results of flow cytometric analysis of nucleated erythroid cell apoptosis in spleen (A) and bone marrow (B) after phenylhydrazine (PHZ) administration. miR-144/451−/− mice (n=5) and wild-type (WT) littermates (n=5) were treated with PHZ (120 mg/kg) on days 0 and 1. Splenocytes and bone marrow cells were harvested four days after PHZ injection. Ter119+Hoechst+ cells are nucleated erythroid cells. Annexin V+PI− near IR− cells are early apoptotic cells. Ter119− cells are non-erythroid cells. **P<0.01 (t-test). (C and D) Flow cytometric analysis of early apoptosis rates of spleen (C) and bone marrow (D) nucleated erythroblasts after bleeding. miR-144/451−/− mice (n=5) and WT littermates (n=5) had 0.4 mL of blood drawn on two consecutive days. Splenocytes and bone marrow cells were harvested on day 3. **P<0.01 (t-test). Note: more early apoptotic erythroblasts were seen in miR-144/451−/− mice.
Figure 3. Apoptosis of miR-144/451−/− bone marrow and spleen erythroblasts is increased under other stress conditions. (A and B) Results of flow cytometric analysis of nucleated erythroid cell apoptosis in spleen (A) and bone marrow (B) after phenylhydrazine (PHZ) administration. miR-144/451−/− mice (n=5) and wild-type (WT) littermates (n=5) were treated with PHZ (120 mg/kg) on days 0 and 1. Splenocytes and bone marrow cells were harvested four days after PHZ injection. Ter119+Hoechst+ cells are nucleated erythroid cells. Annexin V+PI− near IR− cells are early apoptotic cells. Ter119− cells are non-erythroid cells. **P<0.01 (t-test). (C and D) Flow cytometric analysis of early apoptosis rates of spleen (C) and bone marrow (D) nucleated erythroblasts after bleeding. miR-144/451−/− mice (n=5) and WT littermates (n=5) had 0.4 mL of blood drawn on two consecutive days. Splenocytes and bone marrow cells were harvested on day 3. **P<0.01 (t-test). Note: more early apoptotic erythroblasts were seen in miR-144/451−/− mice.CC BY-NC · PubMed Central
Figure 4. miR-451 targets Cab39 mRNA in erythroblasts. (A) Nucleotide sequence alignments showing partial complementarity between the mouse and human 3′-UTRs of Cab39 mRNAs and miR-451. The miR-451 seed-sequence recognition sites in the mRNAs are boxed in white. (B) Fold change in the Cab39 mRNA level from quantitative RT-PCR analysis. Ter119+ nucleated cells were sorted from bone marrow, and a microarray was performed using an Affymetrix GeneChip.15 N=3 mice were used. **P<0.01 (t-test). (C) Cab39 protein levels in both spleen and bone marrow miR-144/451−/− erythroblasts were increased relative to those in wild-type (+/+, WT) controls (top). Ter119+ cells were purified from bone marrow, and whole-cell lysates were analyzed via Western blots with the Cab39 antibody. Representative results for 2 mice of each genotype are shown. (Bottom) Quantitative image analysis from multiple experiments. (D) Cab39 protein levels in miR-144/451−/− fetal liver (FL) erythroblasts were increased relative to those in WT controls (top). (Bottom) Quantitative image analysis for 3 WT and 6 miR-144/451−/− (KO) FLs. (E) G1E proerythroblast cells were transduced with retrovirus encoding miR-451 or empty vector as control. Transduced cells were selected with puromycin and analyzed for Cab39 via Western blots. (Top) Results of a representative experiment and (Bottom) of a quantitative analysis of the Western blot signal intensity from 3 independent experiments. **P<0.01 (t-test). (F) Interaction between miR-451 and the Cab39 3′-UTR inhibits the expression of a linked reporter gene. Firefly luciferase cDNA was fused to the normal 3′-UTR of Cab39 cDNA or a mutant version (mt) containing a 3-bp mutation within the region complementary to the miR-451 seed sequence. The reporter constructs were cloned into an expression vector and transfected into 293T cells, along with an miR-451 expression construct and a constitutively active Renilla luciferase control plasmid. Luciferase activities were determined 24 hours post transfection. (Bottom) Bars represent the Firefly/Renilla luciferase activity; levels from the reporter vector lacking the Cab39 3′-UTR were assigned an arbitrary value of 1. Results are given as the average of 3 separate experiments. **P<0.01 (t-test). Hsa: human; Mmu: mouse.
Figure 4. miR-451 targets Cab39 mRNA in erythroblasts. (A) Nucleotide sequence alignments showing partial complementarity between the mouse and human 3′-UTRs of Cab39 mRNAs and miR-451. The miR-451 seed-sequence recognition sites in the mRNAs are boxed in white. (B) Fold change in the Cab39 mRNA level from quantitative RT-PCR analysis. Ter119+ nucleated cells were sorted from bone marrow, and a microarray was performed using an Affymetrix GeneChip.15 N=3 mice were used. **P<0.01 (t-test). (C) Cab39 protein levels in both spleen and bone marrow miR-144/451−/− erythroblasts were increased relative to those in wild-type (+/+, WT) controls (top). Ter119+ cells were purified from bone marrow, and whole-cell lysates were analyzed via Western blots with the Cab39 antibody. Representative results for 2 mice of each genotype are shown. (Bottom) Quantitative image analysis from multiple experiments. (D) Cab39 protein levels in miR-144/451−/− fetal liver (FL) erythroblasts were increased relative to those in WT controls (top). (Bottom) Quantitative image analysis for 3 WT and 6 miR-144/451−/− (KO) FLs. (E) G1E proerythroblast cells were transduced with retrovirus encoding miR-451 or empty vector as control. Transduced cells were selected with puromycin and analyzed for Cab39 via Western blots. (Top) Results of a representative experiment and (Bottom) of a quantitative analysis of the Western blot signal intensity from 3 independent experiments. **P<0.01 (t-test). (F) Interaction between miR-451 and the Cab39 3′-UTR inhibits the expression of a linked reporter gene. Firefly luciferase cDNA was fused to the normal 3′-UTR of Cab39 cDNA or a mutant version (mt) containing a 3-bp mutation within the region complementary to the miR-451 seed sequence. The reporter constructs were cloned into an expression vector and transfected into 293T cells, along with an miR-451 expression construct and a constitutively active Renilla luciferase control plasmid. Luciferase activities were determined 24 hours post transfection. (Bottom) Bars represent the Firefly/Renilla luciferase activity; levels from the reporter vector lacking the Cab39 3′-UTR were assigned an arbitrary value of 1. Results are given as the average of 3 separate experiments. **P<0.01 (t-test). Hsa: human; Mmu: mouse.CC BY-NC · PubMed Central
Figure 5. Activation of the Cab39/AMPK/mTOR pathway in miR-144/451−/− erythroblasts. (A) Schematic illustration of the major signaling components in the Cab39/AMPK/mTOR molecular pathway. Cab39 expression leads to increased LKB1 activity in the Cab39/LKB1/STRAD protein complex, which activates its substrate AMPK. AMPK activation is vital for modulation of the mTOR signaling cascade and for potential stabilization of p53 activity, which subsequently governs the fate of the target cells, including their apoptosis, survival, and/or proliferation. (B) Western blot analysis of the expression of Cab39, p-AMPKα, p-Raptor, p-TSC2, p-p70S6K, p-S6, and p-eIF4B, along with their non-phosphorylated counterparts, in fetal liver (FL) erythroblasts grown in maturation medium for 24 hours, when all the cells were nucleated erythroblasts. 14-3-3ζ was used as a positive control, and actin was used as a sample loading control. Quantitative analyses of the protein intensity are shown in (C-I) as follows: (C) Cab39, (D) p-AMPKα/AMPKα, (E) p-Raptor/Raptor, (F) p-TSC2/TSC2, (G) p-p70S6K/p70S6K, (H) p-S6/S6, and (I) p-eIF4B/eIF4B. Signals were normalized to actin. Data are the mean values from 3 separate experiments. *P<0.05; **P<0.01 (t-test).
Figure 5. Activation of the Cab39/AMPK/mTOR pathway in miR-144/451−/− erythroblasts. (A) Schematic illustration of the major signaling components in the Cab39/AMPK/mTOR molecular pathway. Cab39 expression leads to increased LKB1 activity in the Cab39/LKB1/STRAD protein complex, which activates its substrate AMPK. AMPK activation is vital for modulation of the mTOR signaling cascade and for potential stabilization of p53 activity, which subsequently governs the fate of the target cells, including their apoptosis, survival, and/or proliferation. (B) Western blot analysis of the expression of Cab39, p-AMPKα, p-Raptor, p-TSC2, p-p70S6K, p-S6, and p-eIF4B, along with their non-phosphorylated counterparts, in fetal liver (FL) erythroblasts grown in maturation medium for 24 hours, when all the cells were nucleated erythroblasts. 14-3-3ζ was used as a positive control, and actin was used as a sample loading control. Quantitative analyses of the protein intensity are shown in (C-I) as follows: (C) Cab39, (D) p-AMPKα/AMPKα, (E) p-Raptor/Raptor, (F) p-TSC2/TSC2, (G) p-p70S6K/p70S6K, (H) p-S6/S6, and (I) p-eIF4B/eIF4B. Signals were normalized to actin. Data are the mean values from 3 separate experiments. *P<0.05; **P<0.01 (t-test).CC BY-NC · PubMed Central
Figure 6. Attenuation of Cab39/AMPK/mTOR signaling rescues erythroid apoptosis after miR-144/451 depletion. (A) shRNA suppression of Cab39 in miR-144/451−/− erythroblasts as shown by Western blot. (B) Apoptosis was measured by flow cytometry, using Annexin V as an indicator. Cab39 shRNA-expressing nucleated erythroblasts were indicated as Ter119+Hoechst+ cells. (C) The apoptotic index in nucleated erythroid cells after knockdown of Cab39. Luciferase (luc) shRNA was used as a negative knockdown control. **P<0.01 (t-test). N=5 fetal liver (FL) erythroblasts of each genotype were used. (D) shRNA suppression of AMPKα in miR-144/451−/− erythroblasts, as shown by Western blot. (E) The percentage of apoptotic nucleated erythroblasts after knockdown of AMPKα. **P<0.01 (t-test). N=4 FLs of each genotype were used. (F) shRNA suppression of TSC2 in miR-144/451−/− erythroblasts, as shown by Western blot. (G) The apoptotic rates of nucleated erythroblasts after knockdown of TSC2. **P<0.01 (t-test). N=4 FLs of each genotype were used.
Figure 6. Attenuation of Cab39/AMPK/mTOR signaling rescues erythroid apoptosis after miR-144/451 depletion. (A) shRNA suppression of Cab39 in miR-144/451−/− erythroblasts as shown by Western blot. (B) Apoptosis was measured by flow cytometry, using Annexin V as an indicator. Cab39 shRNA-expressing nucleated erythroblasts were indicated as Ter119+Hoechst+ cells. (C) The apoptotic index in nucleated erythroid cells after knockdown of Cab39. Luciferase (luc) shRNA was used as a negative knockdown control. **P<0.01 (t-test). N=5 fetal liver (FL) erythroblasts of each genotype were used. (D) shRNA suppression of AMPKα in miR-144/451−/− erythroblasts, as shown by Western blot. (E) The percentage of apoptotic nucleated erythroblasts after knockdown of AMPKα. **P<0.01 (t-test). N=4 FLs of each genotype were used. (F) shRNA suppression of TSC2 in miR-144/451−/− erythroblasts, as shown by Western blot. (G) The apoptotic rates of nucleated erythroblasts after knockdown of TSC2. **P<0.01 (t-test). N=4 FLs of each genotype were used.CC BY-NC · PubMed Central
Figure 7. The increased apoptosis of miR-144/451−/− erythroblasts is p53-dependent. (A) Western blot showing the protein levels of the tumor suppressor p53 in wild-type (WT) and miR-144/451−/− (KO) E14.5 fetal liver (FL) cells. Lineage negative-selected WT and KO E14.5 FL cells were grown in culture in erythroid maturation medium, and cells were harvested for Western blot analysis for p53 after 24 hours in culture. Actin was used as the loading control. (B) Gross view of the cell pellets from miR-144/451−/− and miR-144/451−/−/p53 knock-in (KI) double-mutant E14.5 FLs. (C) Total erythroblast number for whole E14.5 FLs from miR-144/451−/− and miR-144/451−/−/p53 KI double-mutant mice. miR-144/451−/− mice were crossed with p53-deficient KI mice.16,31 N=3 WT mice, n=6 KO mice, and n=6 double-mutant mice were used. **P<0.01 (t-test). (D) Flow cytometric analysis of apoptosis for miR-144/451−/− and miR-144/451−/−/p53 KI double-mutant E14.5 FL cells. WT FLs were used as controls. PI−Annexin V+ labeling was taken to indicate early apoptotic cells. (E) Quantitative analysis of flow cytometric data from (D).
Figure 7. The increased apoptosis of miR-144/451−/− erythroblasts is p53-dependent. (A) Western blot showing the protein levels of the tumor suppressor p53 in wild-type (WT) and miR-144/451−/− (KO) E14.5 fetal liver (FL) cells. Lineage negative-selected WT and KO E14.5 FL cells were grown in culture in erythroid maturation medium, and cells were harvested for Western blot analysis for p53 after 24 hours in culture. Actin was used as the loading control. (B) Gross view of the cell pellets from miR-144/451−/− and miR-144/451−/−/p53 knock-in (KI) double-mutant E14.5 FLs. (C) Total erythroblast number for whole E14.5 FLs from miR-144/451−/− and miR-144/451−/−/p53 KI double-mutant mice. miR-144/451−/− mice were crossed with p53-deficient KI mice.16,31 N=3 WT mice, n=6 KO mice, and n=6 double-mutant mice were used. **P<0.01 (t-test). (D) Flow cytometric analysis of apoptosis for miR-144/451−/− and miR-144/451−/−/p53 KI double-mutant E14.5 FL cells. WT FLs were used as controls. PI−Annexin V+ labeling was taken to indicate early apoptotic cells. (E) Quantitative analysis of flow cytometric data from (D).CC BY-NC · PubMed Central

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Metadata

Authors
Fang, X., Shen, F., Lechauve, C., Xu, P., Zhao, G., Itkow, J., Wu, F., Hou, Y., Wu, X., Yu, L., Xiu, H., Wang, M., Zhang, R., Wang, F., Zhang, Y., Wang, D., Weiss, M. J., & Yu, D.
Venue
Haematologica
Publisher
Ferrata Storti Foundation (Haematologica)
Published
2017-12-21
Volume
103
Issue
3
Pages
406-416
ISSN
  • 0390-6078
  • 1592-8721
DOI
10.3324/haematol.2017.177394
PMC
PMC5830375
Cited by
47
References
5
Language
en

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