Drosha controls dendritic cell development by cleaving messenger RNAs encoding inhibitors of myelopoiesis

Johanson, Timothy M.; Keown, Ashleigh A.; Cmero, Marek; Yeo, Janet H. C.; Kumar, Amit; Lew, Andrew M.; Zhan, Yifan; Chong, Mark M.W.

doi:10.1038/ni.3293

Cited by 35 publications

(68 citation statements)

References 50 publications

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“…Recent reports suggest a function for Drosha in degradation of certain mRNAs that contain pri-miRNA-like stem-loop structures (54–58). It is intriguing to hypothesize that c-Drosha targets a novel set of RNA transcripts, mRNAs for example and regulates their stabilities.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Drosha activity generated by alternative splicing

et al. 2016

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RNase III enzyme Drosha interacts with DGCR8 to form the Microprocessor, initiating canonical microRNA (miRNA) maturation in the nucleus. Here, we re-evaluated where Drosha functions in cells using Drosha and/or DGCR8 knock out (KO) cells and cleavage reporters. Interestingly, a truncated Drosha mutant located exclusively in the cytoplasm cleaved pri-miRNA effectively in a DGCR8-dependent manner. In addition, we demonstrated that in vitro generated pri-miRNAs when transfected into cells could be processed to mature miRNAs in the cytoplasm. These results indicate the existence of cytoplasmic Drosha (c-Drosha) activity. Although a subset of endogenous pri-miRNAs become enriched in the cytoplasm of Drosha KO cells, it remains unclear whether pri-miRNA processing is the main function of c-Drosha. We identified two novel in-frame Drosha isoforms generated by alternative splicing in both HEK293T and HeLa cells. One isoform loses the putative nuclear localization signal, generating c-Drosha. Further analysis indicated that the c-Drosha isoform is abundant in multiple cell lines, dramatically variable among different human tissues and upregulated in multiple tumors, suggesting that c-Drosha plays a unique role in gene regulation. Our results reveal a new layer of regulation on the miRNA pathway and provide novel insights into the ever-evolving functions of Drosha.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic Drosha activity generated by alternative splicing

et al. 2016

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“…The microprocessor interactome has been defined in human embryonic stem cells and indicates the importance of cell-type and biological context (Seong et al, 2014). However, it is clear that several mRNAs are processed by the microprocessor resulting in their destabilization Johanson et al, 2015;Knuckles et al, 2012). The non-canonical functions of the microprocessor represent a rapid and efficient way to influence gene expression.…”

Section: Discussionmentioning

confidence: 99%

Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

et al. 2016

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SUMMARYMulti-lineage neuronal, astrocytic and oligodendrocytic potential is considered a neural stem cell (NSC) trait. However, hippocampal NSCs generate neurons and astrocytes but not oligodendrocytes in vivo and how this is regulated is unknown. Here we show that the RNAseIII Drosha is an intrinsic regulator of stem cell maintenance and differentiation in the adult mouse hippocampus. Inactivation of Drosha results in exhaustion of the NSC pool, premature arrest of neurogenesis, and induction of oligodendrocyte fate commitment. Drosha silences Nuclear Factor IB (NFIB) in hippocampal NSCs by targeting a double-stranded hairpin in the NFIB mRNA, thereby repressing its expression in a Dicer and miRNA-independent manner. We show that NFIB is required and sufficient for oligodendrocyte fate and knockdown of NFIB rescues neurogenesis by Drosha-deficient hippocampal NSCs. Our findings reveal a novel mechanism for stem cell maintenance and oligodendrocyte fate restriction in the adult hippocampus.3

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“…Drosha and DGCR8 are therefore important for maintaining the self‐renewal property of murine neural progenitors, which is achieved by destabilisation of transcripts that encode differentiation factors. In addition to neurogenesis, Drosha is implicated in myeloid development wherein it directly destabilises Myosin Light Chain 9 ( Myl9) mRNA and target of Drosha 1 ( Todr1 ) mRNA, whose protein products are inhibitors of myelopoiesis and are essential for the development of dendritic cells .…”

Section: Drosha and Dgcr8 In Mrna Destabilisationmentioning

confidence: 99%

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

2018

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MicroRNAs (miRNAs) are small regulatory noncoding RNAs that are generated in the canonical RNA interference (RNAi) pathway. Drosha, DiGeorge syndrome critical region 8 (DGCR8) and Dicer are key players in miRNA biogenesis. Argonaute (Ago) proteins bind to miRNAs and are guided by them to find messenger RNA targets and carry out post-transcriptional silencing of protein-coding genes. Recently, emerging evidence suggests that RNAi factors have a range of noncanonical functions that are beyond miRNA biogenesis. These functions pertain to various biological processes, such as development, transcriptional regulation, RNA processing and maintenance of genome integrity. Here, we review recent literature reporting miRNA-independent, noncanonical functions of Drosha, DGCR8, Dicer and Ago proteins and discuss the importance of these functions.

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Drosha controls dendritic cell development by cleaving messenger RNAs encoding inhibitors of myelopoiesis

Cited by 35 publications

References 50 publications

Cytoplasmic Drosha activity generated by alternative splicing

Cytoplasmic Drosha activity generated by alternative splicing

Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

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