Drosha and Dicer are enzymes required for microRNA biogenesis. By genetic ablation in mice, we found that Drosha is critical for the development of dendritic cells (DCs) and other myeloid lineages. Drosha deficiency resulted in a block early in DC development, leading to an accumulation of early haematopoietic progenitors in the bone marrow, and a near total absence of mature DCs in the periphery. In contrast, Dicer deficiency only partially affected DC numbers, and had no impact on haematopoietic progenitors. This suggests that the impact of Drosha deficiency on DC development is largely independent of the microRNA pathway.
In addition to the cleavage of microRNA precursors, our lab and others discovered that Drosha is capable of directly degrading specific messenger RNAs (mRNAs). This occurs via the recognition and cleavage of stem loop structures within the target mRNA. Transcriptional profiling of haematopoietic progenitors revealed a series of transcripts that accumulated upon Drosha, but not Dicer deletion, suggesting microRNA independent regulation. We showed that the derepression of two of these transcripts, Myl9 and 2610318N02Rik is responsible for the block in DC development in the absence of Drosha. Furthermore, we demonstrated that these two transcripts are specific targets of, and are directly cleaved by, Drosha in haematopoietic progenitors. Thus, Drosha is required for DC development through degrading inhibitors of myelopoiesis. This is the first demonstration of a microRNA independent function for Drosha in the haematopoietic system.