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Purpose: Despite the identification of a small population of cells residing in the ciliary body (CB) of the adult mammalian eye that have the capacity to generate retina-like cells in vitro, their activity in vivo remains quiescent. The authors sought to identify whether the predictable and time-dependent death of retinal ganglion cells (RGCs) results in activation of progenitor-like cells within the CB., Methods: RGC injury was induced by optic nerve axotomy in adult mice. Thymidine-analogue lineage tracing and immunocytochemistry were used to identify dividing cells and the phenotype of newly generated progeny., Results: Two populations of nestin-expressing cells are present in the CB of the uninjured eye. One population resides in periendothelial cells of blood vessels, and a second resides in the ciliary epithelium. Axotomy increases proliferation in the CB, a response that begins before the onset of RGC death and continues during a time that corresponds with the peak in RGC death. In addition, a subpopulation of nestin-positive cells in the CB upregulates the homeodomain protein Chx10. Finally, recoverin, the expression of which is normally restricted to photoreceptors and bipolar cells of the retina, is upregulated in the CB in a manner that is independent of proliferation., Conclusions: Together, these results suggest that progenitorlike cells of the CB respond to cues associated with the loss of a single retinal cell type and that a subpopulation of those cells may differentiate into a cell that bears phenotypic resemblance to those seen in the retina.

Recent work in neuroscience has shown that the adult central nervous system (CNS) contains neural progenitors, precursors and stem cells that are capable of generating new neurons, astrocytes and oligodendrocytes. While challenging the previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them the future possibilities for development of novel neural repair strategies. The purpose of this review is to present the current knowledge about constitutively occurring adult mammalian neurogenesis, highlight the critical differences between 'neurogenic' and 'non-neurogenic' regions in the adult brain, and describe the cardinal features of two well-described neurogenic regions-the subventricular zone/olfactory bulb system and the dentate gyrus of the hippocampus. We also provide an overview of presently used models for studying neural precursors in vitro, mention some precursor transplantation models and emphasize that, in this rapidly growing field of neuroscience, one must be cautious with respect to a variety of methodological considerations for studying neural precursor cells both in vitro and in vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims towards molecular and cellular manipulation of endogenous neural precursors in situ, without transplantation. We conclude this review with a discussion of what might be the function of newly generated neurons in the adult brain, and provide a summary of present thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease.

The misfolding of the prion protein (PrP(c)) is a central event in prion diseases, yet the normal function of PrP(c) remains unknown. PrP(c) has putative roles in many cellular processes including signaling, survival, adhesion, and differentiation. Given the abundance of PrP(c) in the developing and mature mammalian CNS, we investigated the role of PrP(c) in neural development and in adult neurogenesis, which occurs constitutively in the dentate gyrus (DG) of the hippocampus and in the olfactory bulb from precursors in the subventricular zone (SVZ)/rostral migratory stream. In vivo, we find that PrP(c) is expressed immediately adjacent to the proliferative region of the SVZ but not in mitotic cells. In vivo and in vitro studies further find that PrP(c) is expressed in multipotent neural precursors and mature neurons but is not detectable in glia. Loss- and gain-of-function experiments demonstrate that PrP(c) levels correlate with differentiation of multipotent neural precursors into mature neurons in vitro and that PrP(c) levels positively influence neuronal differentiation in a dose-dependent manner. PrP(c) also increases cellular proliferation in vivo; in the SVZ, PrP(c) overexpresser (OE) mice have more proliferating cells compared with wild-type (WT) or knockout (KO) mice; in the DG, PrP(c) OE and WT mice have more proliferating cells compared with KO mice. Our results demonstrate that PrP(c) plays an important role in neurogenesis and differentiation. Because the final number of neurons produced in the DG is unchanged by PrP(c) expression, other factors must control the ultimate fate of new neurons.

Recent work in neuroscience has shown that the adult central nervous system contains neural progenitors, precursors, and stem cells that are capable of generating new neurons, astrocytes, and oligodendrocytes. While challenging previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them future possibilities for the development of novel neural repair strategies. The purpose of this review is to present current knowledge about constitutively occurring adult mammalian neurogenesis, to highlight the critical differences between "neurogenic" and "non-neurogenic" regions in the adult brain, and to describe the cardinal features of two well-described neurogenic regions-the subventricular zone/olfactory bulb system, and the dentate gyrus of the hippocampus. We also provide an overview of currently used models for studying neural precursors in vitro, mention some precursor transplantation models, and emphasize that, in this rapidly growing field of neuroscience, one must take caution with respect to a variety of methodological considerations for studying neural precursor cells both in vitro and in vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims toward molecular and cellular manipulation of endogenous neural precursors in situ, without transplantation. We conclude this review with a discussion of what the function might be of newly generated neurons in the adult brain and provide a summary of current thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease.

Over most of the past century of modern neuroscience, it was thought that the adult brain was completely incapable of generating new neurons. During the past 3 decades, research exploring potential neuronal replacement therapies has focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain. However, in the last decade, the development of new techniques has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain. Recent advances in our understanding of related events of neural development and plasticity, including the role of radial glia in developmental neurogenesis and the ability of endogenous precursors present in the adult brain to be induced to produce neurons and partially repopulate brain regions affected by neurodegenerative processes, have led to fundamental changes in the views about how the brain develops as well as to approaches by which endogenous precursors might be recruited to repair the adult brain. Recruitment of new neurons can be induced in a region-specific, layer-specific and neuronal-type-specific manner, and, in some cases, newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow the development of neuronal replacement therapies for neurodegenerative disease and other CNS injuries that do not require transplantation of exogenous cells., (Copyright 2004 S. Karger AG, Basel.)

New neuroblasts are constantly generated in the adult mammalian subventricular zone (SVZ) and migrate via the very-restricted rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into functional neurons. Several facilitating and repulsive molecules for this migration have been identified, but little is known about chemoattractive molecules involved in the directed nature of this migration in vivo. Here, we investigated the role of the alpha6beta1 integrin, and its ligand, laminin, in controlling guidance of the migrating neuroblasts in adult mice. Immunostaining for the alpha6beta1 integrin was present in neuroblasts and their processes in the anterior/rostral SVZ and the RMS. Inhibition of the endogenous alpha6 or beta1 subunit with locally injected antibodies disrupted the cohesive nature of the RMS, but did not kill the neuroblasts. Infusion of a 15 a.a. peptide, representing the E8 domain of the laminin alpha chains that bind alpha6beta1 integrin, into the neostriatum redirected the neuroblasts away from the RMS towards the site of infusion. Injection of a narrow tract of intact laminin also drew the neuroblasts away from the RMS, but in a more restricted localization. These results suggest a critical role for integrins and laminins in adult SVZ-derived neuroblast migration. They also suggest that integrin-based strategies could be used to direct or restrict neuroblasts to CNS regions where they are needed for cell replacement therapies in the nervous system.

In the adult forebrain, new neuroblasts constantly migrate from the subventricular zone along the rostral migratory stream to the olfactory bulb, where many become neurons. It is unclear whether this process is different in commonly used mouse strains and whether it is related to olfactory function. Adult male BALB/c, C57BL/6, and 129/S1 (formerly 129SV) mice were tested for olfactory sensitivity plus discrimination, using male mouse urine from the two other strains. BALB/c mice had the greatest olfactory sensitivity, followed by 129/S1, and C57BL/6 mice, by an order of magnitude each. Newly formed cells were pulse-labeled for 3 h with i.p. 5-bromo-2'-deoxyuridine (BrdU) injections and the animals analyzed 24 h later. In 129/S1 mice, a greater proportion of neuroblasts were present closer to the olfactory bulb than in BALB/c mice, followed by C57BL/6 mice. The total number of BrdU-labeled cells did not differ, suggesting differences in migration and not proliferation. The impaired olfactory function in C57BL/6 mice might be caused by the reduced number of neuroblasts that reach the olfactory bulbs. However, olfactory function in BALB/c and 129/S1 mice did not correlate with their putative migration speed, suggesting a more complex nature of cellular processes that contribute to olfactory function. These results caution against comparing studies of olfactory function or neural precursors that use different strains of mice, and question the use of C57BL/6 mice as a "normal" strain or as transgenic background. Perhaps more importantly, the results point to an opportunity to identify genes that regulate olfactory function and neuroblast behavior.