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Mind bomb 1 in the lymphopoietic niches is essential for T and marginal zone B cell development.

Song R, Kim YW, Koo BK, Jeong HW, Yoon MJ, Yoon KJ, Jun DJ, Im SK, Shin J, Kong MP, Kim KT, Yoon K, Kong YY - J. Exp. Med. (2008)

Bottom Line: In addition, the endocytosis of Dll1 was impaired in the Mib1- microenvironment.Moreover, the block in T cell development and the failure of Dll1 endocytosis were also observed in coculture system by Mib1 knockdown.Our study reveals that Mib1 is the essential E3 ligase in T and MZB cell development, through the regulation of Notch ligands in the thymic and splenic microenvironments.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea.

ABSTRACT
Notch signaling regulates lineage decisions at multiple stages of lymphocyte development, and Notch activation requires the endocytosis of Notch ligands in the signal-sending cells. Four E3 ubiquitin ligases, Mind bomb (Mib) 1, Mib2, Neuralized (Neur) 1, and Neur2, regulate the Notch ligands to activate Notch signaling, but their roles in lymphocyte development have not been defined. We show that Mib1 regulates T and marginal zone B (MZB) cell development in the lymphopoietic niches. Inactivation of the Mib1 gene, but not the other E3 ligases, Mib2, Neur1, and Neur2, abrogated T and MZB cell development. Reciprocal bone marrow (BM) transplantation experiments revealed that Mib1 in the thymic and splenic niches is essential for T and MZB cell development. Interestingly, when BM cells from transgenic Notch reporter mice were transplanted into Mib1- mice, the Notch signaling was abolished in the double-negative thymocytes. In addition, the endocytosis of Dll1 was impaired in the Mib1- microenvironment. Moreover, the block in T cell development and the failure of Dll1 endocytosis were also observed in coculture system by Mib1 knockdown. Our study reveals that Mib1 is the essential E3 ligase in T and MZB cell development, through the regulation of Notch ligands in the thymic and splenic microenvironments.

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Reduction of early T cell progenitors in the thymi of MMTV-Cre;Mib1f/f mice. (A) The thymocytes from the littermate control (left) and mutant (right) mice indicated were stained for CD4, CD8, CD44, CD25, CD24, and c-kit. ETPs were identified by CD24 and c-kit expression gated on CD4−CD8−CD25−CD44+ cells. Percentages indicated are mean ± SD from five independent experiments. (B) Leukocytes from the BM (top) and blood (bottom) of the MMTV-Cre;Mib1+/f and MMTV-Cre;Mib1f/f mice were stained for Sca-1 and c-kit gated on lineage-negative cells to identify LSK cells. Numbers indicate representatives of three independent experiments.
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fig3: Reduction of early T cell progenitors in the thymi of MMTV-Cre;Mib1f/f mice. (A) The thymocytes from the littermate control (left) and mutant (right) mice indicated were stained for CD4, CD8, CD44, CD25, CD24, and c-kit. ETPs were identified by CD24 and c-kit expression gated on CD4−CD8−CD25−CD44+ cells. Percentages indicated are mean ± SD from five independent experiments. (B) Leukocytes from the BM (top) and blood (bottom) of the MMTV-Cre;Mib1+/f and MMTV-Cre;Mib1f/f mice were stained for Sca-1 and c-kit gated on lineage-negative cells to identify LSK cells. Numbers indicate representatives of three independent experiments.

Mentions: Although the ETP generation was not disturbed in the Mib2−/−, Neur1−/−, Neur2−/−, and even Neur1−/−;Neur2−/− mice, the MMTV-Cre;Mib1f/f mice exhibited a dramatic decrease of the ETP populations, as compared with the controls (Fig. 3 A). Although the ETP populations in the thymus were markedly decreased, the LSK progenitors in the BM and blood were preserved in the MMTV-Cre;Mib1f/f mice, indicating that the defective ETP generation is not caused by a decrease in LSK progenitors in the BM and blood (Fig. 3 B). Moreover, the ETP generation was also dramatically reduced in the Mx1-Cre;Mib1f/f mice (unpublished data). These results demonstrate that Mib1, among the four E3 ligases, is required for the ETP generation.


Mind bomb 1 in the lymphopoietic niches is essential for T and marginal zone B cell development.

Song R, Kim YW, Koo BK, Jeong HW, Yoon MJ, Yoon KJ, Jun DJ, Im SK, Shin J, Kong MP, Kim KT, Yoon K, Kong YY - J. Exp. Med. (2008)

Reduction of early T cell progenitors in the thymi of MMTV-Cre;Mib1f/f mice. (A) The thymocytes from the littermate control (left) and mutant (right) mice indicated were stained for CD4, CD8, CD44, CD25, CD24, and c-kit. ETPs were identified by CD24 and c-kit expression gated on CD4−CD8−CD25−CD44+ cells. Percentages indicated are mean ± SD from five independent experiments. (B) Leukocytes from the BM (top) and blood (bottom) of the MMTV-Cre;Mib1+/f and MMTV-Cre;Mib1f/f mice were stained for Sca-1 and c-kit gated on lineage-negative cells to identify LSK cells. Numbers indicate representatives of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571928&req=5

fig3: Reduction of early T cell progenitors in the thymi of MMTV-Cre;Mib1f/f mice. (A) The thymocytes from the littermate control (left) and mutant (right) mice indicated were stained for CD4, CD8, CD44, CD25, CD24, and c-kit. ETPs were identified by CD24 and c-kit expression gated on CD4−CD8−CD25−CD44+ cells. Percentages indicated are mean ± SD from five independent experiments. (B) Leukocytes from the BM (top) and blood (bottom) of the MMTV-Cre;Mib1+/f and MMTV-Cre;Mib1f/f mice were stained for Sca-1 and c-kit gated on lineage-negative cells to identify LSK cells. Numbers indicate representatives of three independent experiments.
Mentions: Although the ETP generation was not disturbed in the Mib2−/−, Neur1−/−, Neur2−/−, and even Neur1−/−;Neur2−/− mice, the MMTV-Cre;Mib1f/f mice exhibited a dramatic decrease of the ETP populations, as compared with the controls (Fig. 3 A). Although the ETP populations in the thymus were markedly decreased, the LSK progenitors in the BM and blood were preserved in the MMTV-Cre;Mib1f/f mice, indicating that the defective ETP generation is not caused by a decrease in LSK progenitors in the BM and blood (Fig. 3 B). Moreover, the ETP generation was also dramatically reduced in the Mx1-Cre;Mib1f/f mice (unpublished data). These results demonstrate that Mib1, among the four E3 ligases, is required for the ETP generation.

Bottom Line: In addition, the endocytosis of Dll1 was impaired in the Mib1- microenvironment.Moreover, the block in T cell development and the failure of Dll1 endocytosis were also observed in coculture system by Mib1 knockdown.Our study reveals that Mib1 is the essential E3 ligase in T and MZB cell development, through the regulation of Notch ligands in the thymic and splenic microenvironments.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea.

ABSTRACT
Notch signaling regulates lineage decisions at multiple stages of lymphocyte development, and Notch activation requires the endocytosis of Notch ligands in the signal-sending cells. Four E3 ubiquitin ligases, Mind bomb (Mib) 1, Mib2, Neuralized (Neur) 1, and Neur2, regulate the Notch ligands to activate Notch signaling, but their roles in lymphocyte development have not been defined. We show that Mib1 regulates T and marginal zone B (MZB) cell development in the lymphopoietic niches. Inactivation of the Mib1 gene, but not the other E3 ligases, Mib2, Neur1, and Neur2, abrogated T and MZB cell development. Reciprocal bone marrow (BM) transplantation experiments revealed that Mib1 in the thymic and splenic niches is essential for T and MZB cell development. Interestingly, when BM cells from transgenic Notch reporter mice were transplanted into Mib1- mice, the Notch signaling was abolished in the double-negative thymocytes. In addition, the endocytosis of Dll1 was impaired in the Mib1- microenvironment. Moreover, the block in T cell development and the failure of Dll1 endocytosis were also observed in coculture system by Mib1 knockdown. Our study reveals that Mib1 is the essential E3 ligase in T and MZB cell development, through the regulation of Notch ligands in the thymic and splenic microenvironments.

Show MeSH
Related in: MedlinePlus