Adult Neurogenesis and Neuronal Subtype Specification in the Neocortex
It was long believed that the adult central nervous system (CNS) was incapable of generating new neurons or having neurons added to its post-mitotic circuitry. However, recent development of new experimental techniques and approaches has shown that the adult brain contains neural precursors (sometimes termed “neural stem cells”; comprising partially heterogeneous, fate-restricted progenitors plus theoretical primitive totipotent CNS “stem cells”) that are capable of generating new neurons, astroglia, and oligodendroglia. Understanding the specific controls over the generation of the wide diversity of neuronal subtypes (both projection neurons and local circuit interneurons), each with specific projection/efferent targets, afferent connectivity, functions, and neurotransmitters will be critical, as the field advances, toward directed and controlled differentiation of neural precursors, and toward potential cellular circuit repair for specific nervous system degenerative and acquired diseases of specific neuronal circuitry.
In this review, we provide an overview of prior work on induced neurogenesis in the adult neocortex from endogenous multipotent precursors, and also discuss emerging knowledge regarding a “molecular logic” of combinational molecular-genetic controls over projection neuron subtype specification and differentiation in the developing neocortex. Together, this developmental and regenerative biology – the earlier “proof-of-concept” experiments on induction of neurogenesis, plus the newly and rapidly developing knowledge of pre- and post-mitotic cell-intrinsic transcriptional controls and cell-extrinsic peptide/growth factor controls over subtype specification, differentiation, and connectivity of disease-vulnerable circuit neurons – provides a roadmap toward potential future functional circuit repair of specific projection neuron circuitry of the adult neocortex.
KeywordsOlfactory Bulb Projection Neuron Adult Neurogenesis Neural Precursor Hippocampal Dentate Gyrus
This review was updated, expanded in scope, integrated, and modified from previously published review articles for different readerships, with only minor or no modification of some subsections (Emsley et al., 2005; Sohur et al., 2006; Kishi et al., 2009) and with some information integrated from a much more extensive review of cortical neuron subtype specification (Molyneaux et al., 2007).
This work was partially supported by grants from the National Institutes of Health (NS45523, NS49553, NS41590), the Harvard Stem Cell Institute, the Spastic Paraplegia Foundation, the ALS Association, and the International Rett Syndrome Foundation (IRSF) to J.D.M. N.K. was supported by fellowships from the Japan Society for the Promotion of Science and the Rett Syndrome Research Foundation (now IRSF). U.S.S. was partially supported by fellowships from the CP Repair Research Fund, and the Edward R. and Anne G. Lefler Center. J.G.E. was partially supported by a Heart and Stroke Foundation of Canada Fellowship, a grant from the Paralyzed Veterans of America/Travis Roy Foundation, and a grant from the Children’s Neurobiological Solutions Foundation to J.D.M.
We thank Bradley Molyneaux, Paola Arlotta, Sara Shnider, and Eiman Azim for contributions to subsections of the manuscript to which they also contributed written material.
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