Neural stem cells have long been defined as origin of nervous system development, spontaneously giving rise to the heterogeneous multitude of cells that make up the brain. Remarkably, neural stem cells seem to have the uncanny sense to differentiate at the right time and place, and to the appropriate fate, to produce a complex network consisting of neuronal connections and supportive glial cells.
Indeed, if you culture neural stem cells in a plastic dish, they can be induced to differentiate into neurons and glia resembling a grab bag of cells that looks nothing like the nervous system. It is therefore apparent that some sort of intrinsic regulation is required to enable nervous stem cells to produce a functional nervous system. In the last decade of research, scientists have uncovered a number of growth factors and transcription factors that control stem cell differentiation during nervous system development (Miller&Gauthier, 2007).
An insightful study in 2009 by Dr. Freda Miller from the University of Toronto revealed an epigenetic "driver" that elegantly controls the timing and fate of neural stem cell differentiation in response to extrinsic factors (Wang et al., 2009). The epigenetic "driver" controls stem cell "avatars" to enable well-coordinated differentiation events crucial for the proper development of the nervous system.
The story leading to Dr. Miller’s discovery began nearly 20 years ago, when developmental neuroscientists presented compelling evidence showing that neural stem cells (NSCs) undergo a 2-stage differentiation program to generate first neurons, and then second glial cells during later stages of nervous system development (Bayer&Altman, 1991). Further studies in the last two decades revealed that this differentiation switch from neurons to glial cells was due in part to differential extrinsic factors expressed at early versus late stages of nervous system development.
One such extrinsic factor is the gliogenic cytokine cardiotrophin-1 (CT-1), which is produced by neurons that were generated during the early stage of nervous system development to drive the onset of NSC differentiation into the glial cell lineage (Barnabe-Heider et al., 2005). The only problem with this model is that gliogenesis was never observed at the onset of neurogenesis where newborn neurons begin producing cardiotrophin (Umerura et al., 2002), but rather after the completion of neurogenesis (Miller and Gauthier, Review, 2007).
It is therefore apparent that the responsiveness of NSCs to neurogenic and gliogenic cytokines is likely regulated by some form of intrinsic program. Recent studies revealed that the central component of this intrinsic program might be chromatin-modifying enzymes (Wang et al., 2009).
Chromatins are densely packaged DNA wrapped around proteins called histones, and can be described as highly dynamic structures that could regulate gene expression simply by differentially restricting transcription enzymes access to their target genes. The chromatin structure could change in response to DNA methylation and histone modifications, which is mediated by a wide range of chromatin modifying enzymes. Among the chromatin modifying enzymes is the histone acetylase called CREB binding protein (CBP), an enzyme that is expressed in neural stem cells.
According to observation by Dr. Freda Miller’s group (Wang et al., 2009), CBP is activated via the atypical protein kinase C pathway- a signalling pathway normally activated in response to extrinsic factors driving neuronal and glial differentiation. Remarkably, the level of CBP activity could govern neural stem cell fate, where neuronal and glial fate are favoured by low and high CBP activity respectively.
Overall, this recent study suggests that CBP could be the epigenetic gauge or "driver" that tells neural stem cell "avatars" how to respond to differentiation cues during the course of nervous system development. This discovery provides a rare glimpse of the complex intrinsic machinery controlling neural stem cell coordination crucial for the proper development of the nervous system.
Barnabe-Heider et al (2005). Neuron. 48, 235-265.
Bayer&Altman (1991). Neocortical Development (New York: Raven Press).
Miller&Gauthier (2007). Neuron. 54, 357-369.
Wang et al (2009). Developmental Cell. 18, 114-125.
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