Arnold Kriegstein, MD, PhD
Arnold Kriegstein, MD, PhD
Neural Stem Cells and Embryonic Cortical Development
Our lab is using electrophysiological, optical recording, and molecular biological approaches to study intercellular signaling and proliferation in the embryonic cerebral cortex during fetal stages of development. Findings from the laboratory reveal that embryonic neuronal stem cells appear to be highly interactive, communicating with each other directly through gap junction channels and responding to their local environment through specific neurotransmitter receptors.
In addition, we demonstrated that radial glial cells, present only in the embryonic and fetal developing brain and long thought to simply guide embryonic nerve cells during migration, are neuronal stem cells in the developing brain. We found that radial glial cells undergo self-renewing, asymmetric divisions to produce nerve cells that often climb along their parent radial glial cells to reach the developing cerebral cortex. This finding suggests that a radial glial 'mother' cell generates and guides daughter neurons. Subsequently, we found that radial glia produce a second nerve cell precursor, an intermediate progenitor cell, that undergoes a different, symmetrical, mode of cell division in a distinct proliferative zone, the subventricular (SVZ) zone to increase neuron number. This suggests new mechanisms for the generation of cell diversity in the developing cortex. The identification of the radial glial cell as a key neuronal stem cell in the developing brain has helped shift attention to the role of glial cells as neuronal stem cells in the adult brain, and has the potential to lead to innovative therapies aimed treating diseases of brain injury.
Unlike the developing rodent cortex, the developing human cortex contains a massively expanded outer SVZ (OSVZ) that is thought to account for the bulk of cortical neurogenesis. We recently found that large numbers of radial glia-like cells, we term oRG cells, and intermediate progenitor cells populate the human OSVZ. Using real-time imaging and clonal analysis, we demonstrated that these cells undergo self-renewing asymmetric divisions to generate neuronal progenitor cells that can further proliferate. We have recently found that neurogenic progenitor cells resembling oRG cells are present, though in small numbers, in mouse embryonic neocortex, and arise from asymmetric divisions of radial glia. These results suggest that oRG cells are probably present in all mammals and are not a specialization of a larger brain with increased cortical area. An evolutionary increase in the number of oRG cells and their transit amplifying daughter cells likely amplified neuronal production and contributed to increased cortical size and complexity in the human brain. Moreover, this pattern of neurogenesis suggests strategies for generating large numbers of specific neurons for cell-based therapies.
Noctor, S.C., Flint, A.C., Weissman, T.A., Dammerman, R.S., &Kriegstein, A.R., Neurons derived from radial glial cells establish radial units in neocortex, Nature , 409:714-20, 2001.
Noctor, S. C., Martínez-Cerdeño, V, Ivic, L, Kriegstein, A. R., Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases, Nature Neuroscience , 7:136-44, 2004.
Weissman T.A., Riquelme P.A., Ivic L., Flint A.C., Kriegstein, A.R., Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex, Neuron , 43:647-61, 2004.
Kriegstein AR, Noctor SC, Martinez-Cerdeno. Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nat Rev Neuroscience 2006; 7(11):883-90.