Embryonic stem cell miRNAs and their roles in development and disease.

MicroRNAs have emerged as important modulators of gene expression. Both during development and disease, regulation by miRNAs controls the choice between self-renewal and differentiation, survival and apoptosis and dictates how cells respond to external stimuli. In mouse pluripotent embryonic stem cells, a surprisingly small set of miRNAs, encoded by four polycistronic genes is at the center of such decisions. miR-290-295, miR-302-367, miR-17-92 and miR-106b-25 encode for miRNAs with highly related sequences that seem to control largely overlapping gene sets. Recent studies have highlighted the importance of these miRNAs in the maintenance of 'stemness' and regulation of normal development and have linked the deregulation of their expression to a variety of human diseases.

Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans.

MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.