miRNA activity directs stem cell commitment to a particular fate.

Extra-cellular ligands and cytokines instruct stem cells to pick specific fates and to activate corresponding genetic programs into differentiation. When a stem cell responds to such an external cue, it is first specified to take a particular differentiation route and then becomes irreversibly obliged or committed, to its future fate. Only later, upon full activation of the new genetic program the cell morphology may be modified and new cellular functions will be acquired. Commitment is a critical step in the life of the cell, as it restricts its developmental potential to just a single option. Therefore, fundamental to commitment is the ability to actively block alternative differentiation programs early on. Whereas only a small amount of data is currently available about the molecular mechanisms underlying commitment, we and others previously suggested that miRNA may confer developmental robustness, by repressing developmental programs related to sibling cell types. For example, osteoclasts and macrophages are both descendants of the monocyte lineage related to the mononuclear phagocyte system. Whilst originating from the same hematopoietic precursor, macrophages identify, engulf and kill invading microorganisms, whereas osteoclasts are bone digesting cells. In our recent work, we have explored the function of a miRNA gene, miR155 that is expressed very early upon macrophage commitment. Pathogen associated molecular patterns such as lipopolysaccaride, signal into differentiation of macrophages. When exposed to lipopolysaccaride, macrophages upregulate miR-155 expression, roughly 100-fold. miRNA activity directs stem cell commitment to a particular fate