Visualization of corticofugal projections during early cortical development in a τ-GFP-transgenic mouse

UCLA Semel Institute for Neuroscience, 635 Charles E Young Drive South, Los Angeles, CA 90095-7332, USA.
European Journal of Neuroscience (Impact Factor: 3.18). 02/2007; 25(1):17-30. DOI: 10.1111/j.1460-9568.2006.05258.x
Source: PubMed


The first postmitotic neurons in the developing neocortex establish the preplate layer. These early-born neurons have a significant influence on the circuitry of the developing cortex. However, the exact timing and trajectory of their projections, between cortical hemispheres and intra- and extra-cortical regions, remain unresolved. Here, we describe the creation of a transgenic mouse using a 1.3 kb golli promoter element of the myelin basic protein gene to target expression of a tau-green fluorescent protein (GFP) fusion protein in the cell bodies and processes of pioneer cortical neurons. During embryonic and early neonatal development, the timing and patterning of process extension from these neurons was examined. Analysis of tau-GFP fluorescent fibers revealed that progression of early labeled projections was interrupted unexpectedly by transient pauses at the corticostriatal and telencephalic-diencephalic boundaries before invading the thalamus just prior to birth. After birth the pioneering projections differentially invaded the thalamus, excluding some nuclei, e.g. medial and lateral geniculate, until postnatal days 10-14. Early labeled projections were also found to cross to the contralateral hemisphere as well as to the superior colliculus. These results indicate that early corticothalamic projections appear to pause before invading specific subcortical regions during development, that there is developmental regulation of innervation of individual thalamic nuclei, and that these early-generated neurons also establish early projections to commissural and subcortical targets.

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    • "Once they have reached the internal capsule, these projections also pause in their growth. In the rat, this synchronised pause has been described to occur approximately between E14.5 and E15.5 (Jacobs et al., 2007), concurrently with the peak of AFP levels observed in our experiments (Fig. 1). Moreover, AFP can be found in the amygdala, thalamus, hypothalamus and the internal capsule, within it is inversely correlated with GAP-43 (Fig. 4a–c). "
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    ABSTRACT: We have previously shown that serum albumin controls perinatal rat brain development through the regulation of oleic acid synthesis by astrocytes. In fact, oleic acid synthesized and released by astrocytes promoted neurite growth, neuron migration and the arrangement of prospective synapses. In this work we show that alpha-fetoprotein (AFP) is also present in the brain during embryonic development, its concentrations peaking at E15.5 and at E19.5. However, after E19.5 AFP concentrations plummeted concurrently with a sharp increase in serum albumin concentrations. At E15.5, AFP is present in caudal regions of the brain, particularly in brain areas undergoing differentiation during this period, such as the thalamic reticular nucleus of the thalamus, the hypothalamus, the amygdala and the hippocampus. Albumin was not detected in the brain at E15.5 but stained brain cells substantially on day E19.5, showing a very similar distribution to that of AFP under the same circumstances. The concentrations of free oleic acid in the brain were inversely correlated with those of AFP, suggesting that the signals elicited by AFP and oleic acid can be inversely associated. GAP-43, a marker of axonal growth that is highly expressed by the presence of oleic acid, was not co-localized with AFP except in the marginal zone and areas delimiting the subplate. AFP prevented the increase in GAP-43 expression caused by the presence of oleic acid in neurons in primary culture in vitro and in organotypic cultures of embryonic rat brain ex vivo, suggesting that AFP may modulate the effect of serum albumin on brain development. Copyright © 2015. Published by Elsevier B.V.
    Brain research 07/2015; 1624. DOI:10.1016/j.brainres.2015.07.021 · 2.84 Impact Factor
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    • "In contrast to the dense cortical inputs in dLGN, VGluT1-positive terminals sparsely populated vLGN (Figure 2A,D). To test whether VGluT1-containing cortical terminals in dLGN and vLGN originated from distinct cortical layers, we examined cortical projections in Golli-tau-gfp transgenic mice, in which layer VI cortical neurons (but not layer V neurons) are labeled with Green Fluorescent Protein (GFP) [35,36,42]. As was the case for VGluT1-IR, tau-GFP distribution was so dense in adult dLGN that individual nerve terminals could not be distinguished, even at high magnification in single optical sections of confocal images (Figure 2E,G). "
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    ABSTRACT: Background Mouse visual thalamus has emerged as a powerful model for understanding the mechanisms underlying neural circuit formation and function. Three distinct nuclei within mouse thalamus receive retinal input, the dorsal lateral geniculate nucleus (dLGN), the ventral lateral geniculate nucleus (vLGN), and the intergeniculate nucleus (IGL). However, in each of these nuclei, retinal inputs are vastly outnumbered by nonretinal inputs that arise from cortical and subcortical sources. Although retinal and nonretinal terminals associated within dLGN circuitry have been well characterized, we know little about nerve terminal organization, distribution and development in other nuclei of mouse visual thalamus. Results Immunolabeling specific subsets of synapses with antibodies against vesicle-associated neurotransmitter transporters or neurotransmitter synthesizing enzymes revealed significant differences in the composition, distribution and morphology of nonretinal terminals in dLGN, vLGN and IGL. For example, inhibitory terminals are more densely packed in vLGN, and cortical terminals are more densely distributed in dLGN. Overall, synaptic terminal density appears least dense in IGL. Similar nuclei-specific differences were observed for retinal terminals using immunolabeling, genetic labeling, axonal tracing and serial block face scanning electron microscopy: retinal terminals are smaller, less morphologically complex, and more densely distributed in vLGN than in dLGN. Since glutamatergic terminal size often correlates with synaptic function, we used in vitro whole cell recordings and optic tract stimulation in acutely prepared thalamic slices to reveal that excitatory postsynaptic currents (EPSCs) are considerably smaller in vLGN and show distinct responses following paired stimuli. Finally, anterograde labeling of retinal terminals throughout early postnatal development revealed that anatomical differences in retinal nerve terminal structure are not observable as synapses initially formed, but rather developed as retinogeniculate circuits mature. Conclusions Taken together, these results reveal nuclei-specific differences in nerve terminal composition, distribution, and morphology in mouse visual thalamus. These results raise intriguing questions about the different functions of these nuclei in processing light-derived information, as well as differences in the mechanisms that underlie their unique, nuclei-specific development.
    Neural Development 07/2014; 9(1):16. DOI:10.1186/1749-8104-9-16 · 3.45 Impact Factor
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    • "Scattered Olig2+ cells observed in the subplate layer probably represent the first cortical OPCs, as both O4+ and PDGFRα+ cells have been described in the same region and at the same developmental stages (Rakic and Zecevic, 2003; Jakovcevski et al., 2009). It is possible that the transient subplate layer, which hosts numerous afferent and efferent fibers (McConnell et al., 1989; Kostovic and Rakic, 1990; Jacobs et al., 2007), supports OPCs differentiation (Jakovcevski et al., 2009). As cortical development proceeds, enriched Olig2 expression is observed in the expanded human outer SVZ (Back et al., 2001; Rakic and Zecevic, 2003; Jakovcevski and Zecevic, 2005; Jakovcevski et al., 2009). "
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    ABSTRACT: Function of oligodendrocytes (OLs), myelin forming cells in the CNS, is disrupted in demyelinating diseases such as periventricular leukomalacia or multiple sclerosis. It is, thus, important to better understand factors that can affect generation or differentiation of human OLs. In rodents, Sonic hedgehog (Shh) is influencing expression of Olig2, a helix-loop-helix transcription factor required for development of OLs. In humans, Olig2 is present in cortical progenitors at midgestation, however the role of Shh in the specification of human OLs, including Olig2 positive (Olig2(+)) progenitors, is not fully understood. Here we studied in vitro effects of Shh signaling on proliferation and specification of human cortical Olig2(+) progenitors at midgestation. First, we established that the spatial pattern of Olig2 expression in the human developing CNS, described on cryosections, was preserved in mixed and enriched radial glia cell (RGC) cultures. Next, we demonstrated that in vitro treatment with Shh induced an increase in the number of Olig2(+) progenitors. Shh treatment increased the density of early oligodendrocyte progenitors (OPCs) at the expense of RGC, while the number of late OPCs, did not change. However, inhibition of endogenous Shh with cyclopamine did not reduce the density of Olig2(+) cells, implying the presence of an additional Shh-independent mechanism for OLs generation in vitro. These results suggest that the primary role of Shh signaling in the human dorsal oligodendrogenesis is the expansion and specification of multipotent radial glia progenitors into Olig2(+) early OPCs. These results obtained in vitro are relevant to understand primary myelination during CNS development, as well as remyelination in demyelinating diseases.
    Frontiers in Cellular Neuroscience 12/2013; 7:254. DOI:10.3389/fncel.2013.00254 · 4.29 Impact Factor
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