Stimulating neurogenesis in "non-neurogenic" brain regions
J.G. Emsley
MGH-HMS Center for Nervous System Repair, Departments of Neurosurgery and Neurology, Harvard Stem Cell Institute, Harvard University, Massachusetts General Hospital, Edwards 4 (EDR 410), 50 Blossom Street, Boston MA 02114, USA
Contrary to previously held beliefs about the static nature of the adult mammalian brain, it is in fact capable of generating new neurons that can integrate into its complex circuitry. The recent development of new techniques has resulted in an explosion of research demonstrating that neurogenesis, the birth of new neurons, constitutively occurs in two specific regions of the adult mammalian brain (olfactory bulb and hippocampal dentate gyrus), and that there are significant numbers of multipotent neural precursors, or "stem cells," in many parts of the adult brain.
The rise of precursor cell biology has brought new life to neural transplantation and the consideration of cellular replacement strategies to treat diseases of the brain and spinal cord. The idea of "making new neurons" is appealing for neurodegenerative diseases or selective neuronal loss associated with chronic neurological or psychiatric disorders. Data from our lab demonstrate that new neurons can be added to adult neocortical circuitry from transplanted neural precursors or via manipulation of endogenous precursors in situ (including induction of limited neurogenesis of long-distance cortical projection neurons in adult mice). These data indicate that cellular repair of damaged cortical and cortical output circuitry might be possible, if controls over specific lineage differentiation are understood.
Given the heterogeneity of neuronal subtypes in the complex mammalian cerebral cortex, and the complexity of their connections, attempts to functionally repair neocortical circuitry will require detailed understanding of signals that control differentiation, connectivity, and survival of specific neuronal lineages. Toward these goals, we have identified developmentally regulated transcriptional programs for specific lineages of long-distance projection neurons as they develop in vivo (in particular, for corticospinal motor neurons, callosal projection neurons and, more recently, corticothalamic projection neurons). Loss-and gain-of-function analyses for cortical neuron subtype-specific genes indicate the existence of programs of combinatorial molecular-genetic controls over the precise development of key cortical projection neuron populations. Such information may allow for directed control of neural precursors/stem cells, toward functional CNS repair.
Key words:
cortex, development, neural precursors, neurogenesis, stem cells
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