Coffre Maryaline, Benhamou David, Rieß David, Blumenberg Lili, Snetkova Valentina, Hines Marcus J, Chakraborty Tirtha, Bajwa Sofia, Jensen Kari, Chong Mark M W, Getu Lelise, Silverman Gregg J, Blelloch Robert, Littman Dan R, Calado Dinis, Melamed Doron, Skok Jane A, Rajewsky Klaus, Koralov Sergei B
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Department of Immunology, Faculty of Medicine, Technion, Haifa 31096, Israel.
Cell Rep. 2016 Nov 22;17(9):2271-2285. doi: 10.1016/j.celrep.2016.11.006.
B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.
B细胞发育是一个严格调控的过程，依赖于编码抗原受体的免疫球蛋白基因座的顺序重排。为了阐明微小RNA（miRNA）在B细胞发育调控中的作用，我们通过有条件地靶向早期B细胞前体中对RNA干扰至关重要的酶，在B细胞发育的最早阶段消除了所有miRNA。这些酶中任何一种的缺失都会导致从前B细胞到前B细胞的转变受阻，原因是细胞凋亡增加以及前B细胞增殖失败。Bcl2转基因的表达使得B细胞发育得到部分挽救，然而，大多数挽救的B细胞表面免疫球蛋白表达较低，并有正在进行轻链编辑的证据。我们的分析表明，miRNA对于PTEN-AKT-FOXO1通路的调控至关重要，而该通路反过来又在B细胞发育过程中控制Rag表达。
