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Bcl11a is essential for lymphoid development and negatively regulates p53.

Yu Y, Wang J, Khaled W, Burke S, Li P, Chen X, Yang W, Jenkins NA, Copeland NG, Zhang S, Liu P - J. Exp. Med. (2012)

Bottom Line: Myeloid development, in contrast, is not obviously affected by the loss of Bcl11a.Bcl11a regulates expression of Bcl2, Bcl2-xL, and Mdm2, which inhibits p53 activities.Bcl11a is therefore essential for lymphopoiesis and negatively regulates p53 activities.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China.

ABSTRACT
Transcription factors play important roles in lymphopoiesis. We have previously demonstrated that Bcl11a is essential for normal lymphocyte development in the mouse embryo. We report here that, in the adult mouse, Bcl11a is expressed in most hematopoietic cells and is highly enriched in B cells, early T cell progenitors, common lymphoid progenitors (CLPs), and hematopoietic stem cells (HSCs). In the adult mouse, Bcl11a deletion causes apoptosis in early B cells and CLPs and completely abolishes the lymphoid development potential of HSCs to B, T, and NK cells. Myeloid development, in contrast, is not obviously affected by the loss of Bcl11a. Bcl11a regulates expression of Bcl2, Bcl2-xL, and Mdm2, which inhibits p53 activities. Overexpression of Bcl2 and Mdm2, or p53 deficiency, rescues both lethality and proliferative defects in Bcl11a-deficient early B cells and enables the mutant CLPs to differentiate to lymphocytes. Bcl11a is therefore essential for lymphopoiesis and negatively regulates p53 activities. Deletion of Bcl11a may represent a new approach for generating a mouse model that completely lacks an adaptive immune system.

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Related in: MedlinePlus

Severe defects in B, T, and NK cell precursors and lymphoid progenitor compartments in recipient mice engrafted with Lin− BM cells (CD45.1−). Lethally irradiated recipient mice (CD45.1+) engrafted with BM cells of indicated genotypes were treated with Tam and analyzed 4 wk later (n = 4/group, and the experiment was repeated 4 times). Panels show total cell numbers (bar graphs) and/or flow cytometry dot plots of donor BM B cells (A), donor thymocytes (B), donor BM NK cells (C and D), and donor lymphoid progenitors (E). Numbers in the flow cytometry plots refer to percentages of gated cells in total donor nucleated BM cells or thymocytes. *, P < 0.05; **, P < 0.01.
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fig3: Severe defects in B, T, and NK cell precursors and lymphoid progenitor compartments in recipient mice engrafted with Lin− BM cells (CD45.1−). Lethally irradiated recipient mice (CD45.1+) engrafted with BM cells of indicated genotypes were treated with Tam and analyzed 4 wk later (n = 4/group, and the experiment was repeated 4 times). Panels show total cell numbers (bar graphs) and/or flow cytometry dot plots of donor BM B cells (A), donor thymocytes (B), donor BM NK cells (C and D), and donor lymphoid progenitors (E). Numbers in the flow cytometry plots refer to percentages of gated cells in total donor nucleated BM cells or thymocytes. *, P < 0.05; **, P < 0.01.

Mentions: Compared with the Tam-treated flox/flox mice described above, the flox/flox BM chimeras exhibited similar lymphoid defects when cells were analyzed 1 wk after Tam treatment (unpublished data). However, 4 wk after Tam administration, more severe lymphoid defects were revealed: no pro–B, pre–B, or immature B cells could be detected, and the total BM B cells decreased to 5% of the wild-type (Fig. 3 A). There were also few ETPs or DN2 thymocytes (Fig. 3 B). The longer time window after Bcl11a deletion also revealed a drastic decrease of DN3 and DN4 thymocytes. The complete depletion of Bcl11a-deficient early B cells and thymocytes indicate that these cells either gradually differentiated or died and that they were not replenished from lymphoid progenitors. Additionally, Bcl11a deletion depleted all NK progenitors, and only few NK cells were present in the BM (Fig. 3, C and D).


Bcl11a is essential for lymphoid development and negatively regulates p53.

Yu Y, Wang J, Khaled W, Burke S, Li P, Chen X, Yang W, Jenkins NA, Copeland NG, Zhang S, Liu P - J. Exp. Med. (2012)

Severe defects in B, T, and NK cell precursors and lymphoid progenitor compartments in recipient mice engrafted with Lin− BM cells (CD45.1−). Lethally irradiated recipient mice (CD45.1+) engrafted with BM cells of indicated genotypes were treated with Tam and analyzed 4 wk later (n = 4/group, and the experiment was repeated 4 times). Panels show total cell numbers (bar graphs) and/or flow cytometry dot plots of donor BM B cells (A), donor thymocytes (B), donor BM NK cells (C and D), and donor lymphoid progenitors (E). Numbers in the flow cytometry plots refer to percentages of gated cells in total donor nucleated BM cells or thymocytes. *, P < 0.05; **, P < 0.01.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526365&req=5

fig3: Severe defects in B, T, and NK cell precursors and lymphoid progenitor compartments in recipient mice engrafted with Lin− BM cells (CD45.1−). Lethally irradiated recipient mice (CD45.1+) engrafted with BM cells of indicated genotypes were treated with Tam and analyzed 4 wk later (n = 4/group, and the experiment was repeated 4 times). Panels show total cell numbers (bar graphs) and/or flow cytometry dot plots of donor BM B cells (A), donor thymocytes (B), donor BM NK cells (C and D), and donor lymphoid progenitors (E). Numbers in the flow cytometry plots refer to percentages of gated cells in total donor nucleated BM cells or thymocytes. *, P < 0.05; **, P < 0.01.
Mentions: Compared with the Tam-treated flox/flox mice described above, the flox/flox BM chimeras exhibited similar lymphoid defects when cells were analyzed 1 wk after Tam treatment (unpublished data). However, 4 wk after Tam administration, more severe lymphoid defects were revealed: no pro–B, pre–B, or immature B cells could be detected, and the total BM B cells decreased to 5% of the wild-type (Fig. 3 A). There were also few ETPs or DN2 thymocytes (Fig. 3 B). The longer time window after Bcl11a deletion also revealed a drastic decrease of DN3 and DN4 thymocytes. The complete depletion of Bcl11a-deficient early B cells and thymocytes indicate that these cells either gradually differentiated or died and that they were not replenished from lymphoid progenitors. Additionally, Bcl11a deletion depleted all NK progenitors, and only few NK cells were present in the BM (Fig. 3, C and D).

Bottom Line: Myeloid development, in contrast, is not obviously affected by the loss of Bcl11a.Bcl11a regulates expression of Bcl2, Bcl2-xL, and Mdm2, which inhibits p53 activities.Bcl11a is therefore essential for lymphopoiesis and negatively regulates p53 activities.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China.

ABSTRACT
Transcription factors play important roles in lymphopoiesis. We have previously demonstrated that Bcl11a is essential for normal lymphocyte development in the mouse embryo. We report here that, in the adult mouse, Bcl11a is expressed in most hematopoietic cells and is highly enriched in B cells, early T cell progenitors, common lymphoid progenitors (CLPs), and hematopoietic stem cells (HSCs). In the adult mouse, Bcl11a deletion causes apoptosis in early B cells and CLPs and completely abolishes the lymphoid development potential of HSCs to B, T, and NK cells. Myeloid development, in contrast, is not obviously affected by the loss of Bcl11a. Bcl11a regulates expression of Bcl2, Bcl2-xL, and Mdm2, which inhibits p53 activities. Overexpression of Bcl2 and Mdm2, or p53 deficiency, rescues both lethality and proliferative defects in Bcl11a-deficient early B cells and enables the mutant CLPs to differentiate to lymphocytes. Bcl11a is therefore essential for lymphopoiesis and negatively regulates p53 activities. Deletion of Bcl11a may represent a new approach for generating a mouse model that completely lacks an adaptive immune system.

Show MeSH
Related in: MedlinePlus