MicroRNAs regulate adult neurogenesis

It is now well established that the adult mammalian brain contains stem cells which continue to generate new neurons throughout life. This discovery, and subsequent research, has transformed the way we think about the brain. It is, for example, known that physical and mental exercise can stimulate the growth of new nerve cells in a part of the brain which shrinks in Alzheimer's and depression, and so it is believed that such activities can reduce the risk of both conditions.

Despite all this, little is known about the mechanisms by which neural stem cells are directed to generate neurons. Now researchers from Columbia University Medical Center have found that neurogenesis in the adult mouse brain is regulated by microRNAs, the small nucleic acid molecules which are encoded in those parts of the genome that were often referred to as "junk" DNA.

The adult brain contains at least two populations of stem cells from which new neurons are generated. One of these is found in the dentate gyrus of the hippocampus, a region of the brain which is known to be crucial for memory (and which degenerates in Alzheimer's and depression). Once formed, these neurons are integrated into the circuitry of the hippocampus; their function eluded researchers for many years, bu they are now known to be required for the formation of new memories. The second, and larger, population is in the subventricular zone (SVZ), a proliferative tissue which lines the walls of the lateral ventricles. Neurons generated here migrate within the rostral migratory stream to the olfactory bulb; they, too, are integrated into the existing circuitry, but exactly what they do there is still unclear. 

As well generating new nerve cells and glia, these stem cell populations also maintain themselves. They do so by dividing asymmetrically - each division produces one stem cell and one neuron or glial cell. The fate of a daughter cell is determined genetically after cell division has taken place. One set of genes causes cells to differentiate into immature neurons (neuroblasts), which then set off on their migration and mature on the journey; a second set of genes causes the cells to differentiate into oligodendrocytes, which form a fatty tissue that envelopes axons and increases the velocity at which nervous impulses travel along them; and a third set maintains them as dividing stem cells. Each of these pathways is regulated by proteins called transcription factors, which activate or inhibit specific sets of genes, but the factors which control the different fates of neural stem cells have not been identified.

The transcription factors which determine the fate of a daughter cell are synthesized in the same way as all other proteins. First, a transcript of the DNA coding sequence is produced in the nucleus. This is exported to the cytoplasm, where it can then be translated into a string of amino acids which fold up into a functional protein. MicroRNAs tightly regulate this process, and are now known to repress protein synthesis in at least two ways. They can recognize the transcript of a given gene and destroy it, or bind to it and prevent the protein synthesis machinery from gaining access.    

In the new study, Li-Chun Cheng and her colleagues examined the distribution of miR-124 in SVZ cells and their derivatives. They found that it was found present at low levels in immature neurons in the SVZ and cells moving through the rostral migratory stream, and in high levels in the olfactory bulb. But it was absent from the dividing cells in the SVZ, and closer examination revealed that it is upregulated in those daughter cells which are destined to become neurons, soon after they have been formed by cell division. This suggested that miR-124 plays a role in regulating the differentiation of neural stem cells.

This possibility was investigated in a series of experiments performed on isolated SVZ cells growing in a culture dish. When miR-124 was blocked by the addition of an antisense oligonucleotide to the growth medium, the cells remained in an undifferentiated state - they continued to divide and to increase in number. Conversely, exogenous miR-124 shuttled into the cells on the back of a retrovirus caused a reduction in the number of dividing cells and an increase in the number of neuroblasts. These findings were confirmed in vivo. Significantly, injection of the antisense into the lateral ventricles of mice prevented the SVZ cells from differentiating into neuroblasts, and instead caused the dividing cells to form large, disorganizaed clusters.

The reseachers also identified a number of targets for miR-124. Two of these, Dlx2 and Jag1, are transcription factors already known to be important for neurogenesis in the SVZ. A third trasncription factor, Sox9, was also identified. Sox9 is known to promote glial differentiation and inhibit neuronal differentiation during spinal cord development, but this is the first study to show that it also plays a role in the SVZ. Thus, by binding to Sox9 transcripts and preventing their translation, miR-124 prevents SVZ cells from differentiating into glial cells, and drives them along the pathway to neuronal differentiation instead. But as individual microRNAs have been shown to target hundreds of genes, miR-124 is likely to exert its effects on other transcripts too.  

Stem cells have huge therapeutic potential, and neural stem cells in particular have been suugested as therapies for stroke, Parkinson's Disease and various other conditions. Most efforts have involved the transplantation of stem cells into the damaged area of the brain, but so far researchers have had little success. An alternative approach, which remains to be explored, is to coax the brain's endogenous stem cell populations into proliferating and migrating to where they are needed. However, this is hindered by our lack of understanding of how stem cell activity is regulated. The discovery that microRNAs regulate adult neurogenesis in the SVZ could therefore eventually lead to new strategies for combating other neurological diseases. It also suggests a new approach to inhibiting the growth of brain tumours.

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Cheng, L., et al (2009). miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat. Neurosci. 12: 399-408. DOI: 10.1038/nn.2294.