According to parental advice, children can be whatever they want to be when they grow up. Similarly, researchers believed that neural stem cells could differentiate into any type of brain cell. Now Merkle et al. report that neural stem cells in the postnatal brain are preprogrammed to become specific types of neuron in a recent article in Science.
In the perinatal brain, most stem cells are radial glia, which develop into the astrocyte-like stem cells in the adult brain. These stem cells localize to a region adjacent to the lateral ventricle known as the subventricular zone (SVZ) and produce new neurons (neuroblasts) that migrate to the olfactory bulb in the rostral migratory stream. Neuroblasts were thought to remain identical until they reached the olfactory bulb, where they differentiated.
To challenge this idea, the authors labeled 15 distinct populations of radial glia in the newborn brain. In Z/EG mice, adenoviral vectors expressing Cre recombinase excise a ubiquitous lacZ reporter, inducing the expression of an adjacent green fluorescent protein (GFP) reporter. Adenovirus is transported from neural processes to cell bodies but does not diffuse from the injection site, so only injected cells and their progeny are permanently labeled with GFP.
Each subset of radial glia produced a different subset of interneurons in the olfactory bulb. Adult stem cells differentiate into either periglomerular or granule cell interneurons in the olfactory bulb. Nonoverlapping groups of periglomerular cells express calretinin, calbindin or tyrosine hydroxylase. Granule cells are distinguished by their location in the granule cell layer (deep or superficial) and variable expression of calretinin. Dorsal radial glia populations produced tyrosine hydroxylase-positive periglomerular cells and superficial granule cells. Ventral radial glia populations produced calbindin-positive periglomerular cells and deep granule cells. Radial glia from the medial septal wall and the rostral migratory stream produced calretinin-positive periglomerular and granule cells. The authors labeled several SVZ stem cell populations in the adult brain and found that similarly located stem cells produce the same neuron types in the adult and newborn brain, suggesting that some intrinsic or environmental factor induces region-specific neuron development from neural stem cells in the postnatal brain.
If an environmental factor programs region-specific neuron development, then radial glia transplanted to a new part of the neonatal brain would develop into the type of neuron specified by the new location. However, ventral populations of radial glia developed into superficial granule cells whether they were transplanted in ventral or dorsal positions. Radial glia populations cultured with identical cocktails of neurotrophic factors differentiated in vitro into neuron types designated by their region of origin, as shown by immunocytochemistry. When grafted into donor brains, radial glia cultured alone or with neurons from other brain regions produced their predesignated neuron type, suggesting that an intrinsic factor induces specific neuron development from distinct stem cell popluations in the postnatal brain.
Therefore, neural stem cells are not identical and may require the induction of specific gene programs to differentiate into desired neuron types for stem cell therapies.