The developmental origin of oligodendrocyte progenitors (OLPs) in the forebrain has been controversial. We now show, by Cre-lox fate mapping in transgenic mice, that the first OLPs originate in the medial ganglionic eminence (MGE) and anterior entopeduncular area (AEP) in the ventral forebrain. From there, they populate the entire embryonic telencephalon including the cerebral cortex before being joined by a second wave of OLPs from the lateral and/or caudal ganglionic eminences (LGE and CGE). Finally, a third wave arises within the postnatal cortex. When any one population is destroyed at source by the targeted expression of diphtheria toxin, the remaining cells take over and the mice survive and behave normally, with a normal complement of oligodendrocytes and myelin. Thus, functionally redundant populations of OLPs compete for space in the developing brain. Notably, the embryonic MGE- and AEP-derived population is eliminated during postnatal life, raising questions about the nature and purpose of the competition.

Cortical pyramidal cells are generated from pallial neuroepithelial precursors, whereas GABAergic interneurons originate in subpallial germinal zones and migrate tangentially to reach the cortex. Using Cre-lox technology in transgenic mice and a series of molecular markers that subdivide the subpallial neuroepithelium into small domains, we fate-map precursor pools and identify interneurons generated from each domain. Cortical interneurons expressing calbindin, parvalbumin, and somatostatin are generated exclusively from Lhx6 (Lim homeobox 6)-expressing precursors in the medial ganglionic eminence (MGE). Martinotti cells that coexpress calretinin and somatostatin are generated from the dorsal region of the MGE neuroepithelium that expresses Nkx6.2 (NK2 transcription factor-related 6.2). Most neuropeptide Y-expressing cells and all bipolar calretinin-expressing interneurons are generated outside the MGE, from the germinal zones of the lateral/caudal ganglionic eminences that express Gsh2 (genomic screened homeobox 2). Our data demonstrate that subpallial neuroepithelial domains defined by expression of genetic determinants generate distinct interneuron subtypes, thereby contributing to the generation of cortical interneuron heterogeneity observed in the adult cortex.

We determined the embryonic origins of adult forebrain subventricular zone (SVZ) stem cells by Cre-lox fate mapping in transgenic mice. We found that all parts of the telencephalic neuroepithelium, including the medial ganglionic eminence and lateral ganglionic eminence (LGE) and the cerebral cortex, contribute multipotent, self-renewing stem cells to the adult SVZ. Descendants of the embryonic LGE and cortex settle in ventral and dorsal aspects of the dorsolateral SVZ, respectively. Both populations contribute new (5-bromo-2Ј-deoxyuridine-labeled) tyrosine hydroxylase-and calretinin-positive interneurons to the adult olfactory bulb. However, calbindinpositive interneurons in the olfactory glomeruli were generated exclusively by LGE-derived stem cells. Thus, different SVZ stem cells have different embryonic origins, colonize different parts of the SVZ, and generate different neuronal progeny, suggesting that some aspects of embryonic patterning are preserved in the adult SVZ. This could have important implications for the design of endogenous stem cell-based therapies in the future.

Many oligodendrocytes in the spinal cord are derived from a region of the ventral ventricular zone (VZ) that also gives rise to motoneurons. Cell fate specification in this region depends on sonic hedgehog (Shh) from the notochord and floor plate. There have been suggestions of an additional source(s) of oligodendrocytes in the dorsal spinal cord. We revisited this idea by Cre-lox fate-mapping in transgenic mice. We found that a subpopulation of oligodendrocytes is generated from the Dbx1-expressing domain of the VZ,spanning the dorsoventral midline. Dbx-derived oligodendrocytes comprise less than 5% of the total; they are formed late during embryogenesis by transformation of radial glia and settle mainly in the lateral white matter. Development of Dbx-derived oligodendrocytes in vitro can occur independently of Shh but requires FGF signalling. Dbx-expressing precursors also generate astrocytes and interneurons, but do not contribute to the ependymal layer of the postnatal spinal cord.

Human embryonic stem cells (HESC) are an unlimited source of cells for stem cell therapies. We investigated the dynamics of integration of HESC-derived neural precursors (NPs) into host neural circuitry.Methods: NP cultures were derived from the NIH-approved HESC line BG01 with noggin in B27/N2-supplemented medium. These NPs were grafted into the forebrain and ventral brain stem of immunodeficient rats (NIH-RNU). Brain tissues were prepared at 6, 15 and 26 weeks post-grafting.Results: The HESC-NPs showed a site-dependent fate, i.e. a greater mitotic activity and ongoing neuroepithelial structure formation in the brain stem and a lower mitotic activity and eventual resolution and dedifferentiation of early neuroepithelial structures in the forebrain. The later almost disappeared at 15 weeks post-grafting. By 15 weeks, a large percentage (57.8-80.8%) had differentiated into early (TUJ-1[+]) neurons that extended axons along pre-established CNS pathways (cortico-striatal, internal capsule, external capsule) and formed dense synaptic fields, especially in the graft area in the form of local innervation and in the host subventricular zone (SVZ). An especially strong affinity for SVZ and the pia mater was noted. Some migration was seen along white matter tracts; in the case of ventral brain stem injections, migration of nestin/NCAM (+) precursors could be followed several segments down the cervical cord. The extensive ability of HESC-NPs to differentiate into neurons, migrate and possibly establish synaptic contacts with other graft and host cells demonstrates their potential to repair neural circuits damaged by either trauma or neurodegeneration. The successful outcomes of human NP xenografts in rats demonstrate the value of human-to-rodent experimental approaches in the preclinical evaluation of human ES cells. In addition, HES-NPs may prove to be valuable instruments for studying novel inductive signals that influence not only graft differentiation and integration, but also host repair mechanisms, including neurogenesis and synaptic plasticity after trauma.

Previous studies demonstrated that elevation in the levels of the pro-inflammatory cytokine interleukin-1 (IL-1) within the brain is involved in mediating the memory impairments associated with inflammation and aging. In the present study, we used a model of chronic stress, in which each mouse was isolated in an individual cage for 3 weeks. In both the contextual fear conditioning (FC) test and the spatial version of the Morris water maze (MWM) paradigm, which depend on hippocampal functioning, isolated mice displayed significant memory impairments. Isolation had no effect on the hippocampus independent auditory-cued FC and the non-spatial version of the MWM. Isolation caused a significant elevation in hippocampal IL-1␤ levels as well as a significant decrease in hippocampal neurogenesis. To explore the role of hippocampal IL-1 in stress-induced memory impairments and suppressed neurogenesis, neural precursor cells (NPCs) were isolated from neonatal mice with transgenic over-expression of IL-1 receptor antagonist (IL-1raTG) under the GFAP promoter, labeled with PKH-26 and transplanted into the hippocampus of WT mice. Three weeks later, transplanted cells, expressing mainly astrocytic markers, could be observed within the hippocampus, and the levels of hippocampal IL-1ra were markedly elevated. In isolated mice, transplantation of IL-1raTG NPCs completely rescued the memory impairments and significantly increased hippocampal neurogenesis, compared with isolated mice transplanted with WT cells or sham-operated only. The transplantation had no effect in non-stressed mice.These findings elucidate the role of IL-1 in the pathophysiology of chronic stress and suggest that the intra-hippocampal transplantation of transgenic IL-1raTG NPCs may provide a useful therapeutic procedure for IL-1-mediated memory disturbances in other conditions, particularly neurodegenerative diseases.The embryonic neuroepithelium can be subdivided into at least three domains: the cortical neuroepithelium, the medial ganglionic eminence (MGE) and the lateral ganglionic eminence (LGE). Each region has a specific gene expression pattern and neurogenic potential during embryogenesis. However, the contribution of each embryonic germinal zone to the neural stem cells of the adult subventricular zone (SVZ) has not been clearly defined. To address this question we used four transgenic lines that express Cre recombinase in defined neuroepithelial domains: Gsh2-Cre (to label the LGE and MGE), Nkx2.1-Cre (MGE), Emx1-Cre (cortex) and Dbx1-Cre (cortico-striatal sulcus) (Kessaris et al., 2006;Fogarty et al., 2005). When one of these lines was crossed with a Rosa26-GFP Cre-dependent reporter, GFP was activated in the corresponding neuroepithelial domain and retained in all of its cell progeny, allowing their nature and location to be traced into adulthood. Visualization of GFP in the adult SVZ identified a significant contribution of cells from all parts of the embryonic neuroepithelium, including the cortex. The cortically derived SVZ cells did not result f...