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Blood. 2015 Jun 11;125(24):3720-30. doi: 10.1182/blood-2014-10-603951. Epub 2015 Apr 30.

Altered lymphopoiesis and immunodeficiency in miR-142 null mice.

Author information

1
Department of Molecular and Cellular Biology.
2
Division of Hematopoietic Stem Cell and Leukemia Research.
3
Department of Virology, and.
4
Division of Comparative Medicine, Beckman Research Institute, City of Hope, Duarte, CA; and.
5
Regulus Therapeutics, San Diego, CA.

Abstract

MicroRNAs (miRNAs) are a class of powerful posttranscriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is preferentially and abundantly expressed in immune cells, we created a mouse line with a targeted deletion of this gene. Our analysis of miR-142(-/-) mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, whereas the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142(-/-) animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142(-/-) B cells express elevated levels of B-cell-activating factor (BAFF) receptor (BAFF-R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142(-/-) mice rescues the B-cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B-cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphopoiesis, and suggest that lesions in this miRNA gene may lead to primary immunodeficiency.

PMID:
25931583
DOI:
10.1182/blood-2014-10-603951
[Indexed for MEDLINE]
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