MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate and neurogenesis.

MicroRNAs are small noncoding RNAs that can affect the expression of genes. For example, microRNAs play important roles during the development of the nervous system by regulating the expression of genes involved in neurogenesis. We have found that a microRNA known as let-7d, which has been implicated in cocaine addiction and other neurological disorders, targets a gene called TLX. The protein encoded by the TLX gene is important for maintaining the self-renewal of neural stem cells; if insufficient TLX is present, neural stem cells will stop renewing themselves and will instead differentiate into mature nerve cells. Overexpression of let-7d in neural stem cells in mouse brains reduced the proliferation of these cells and led them to differentiate and migrate prematurely. This effect was similar to that seen when expression of TLX is knocked down or when microRNA-9, which is negatively-regulated by TLX, is overexpressed. We found that let-7d binds to a sequence in the untranslated region at the end of the TLX RNA (this region is known as the 3’ UTR) and that let-7d reduced TLX expression levels in neural stem cells, which in turn, up-regulated miR-9 expression. Moreover, expression of both let-7d and TLX lacking its 3' UTR in neural stem cells in mouse brains restored neural stem cell proliferation. In addition, these cells did not prematurely differentiate and migrate. This suggests that, manipulating let-7d and/or genes that are regulated by let-7d could provide insight into the signaling pathways involved in the conversion and maturation of neural stem cells into neurons, which would provide a better understanding of how the brain works and could identify potential ways to improve treatment of neurological disorders.