Decision by division: Making cortical maps

Department of Neurobiology and Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
Trends in Neurosciences (Impact Factor: 13.56). 05/2009; 32(5):291-301. DOI: 10.1016/j.tins.2009.01.007
Source: PubMed


In the past three decades, mounting evidence has revealed that specification of the basic cortical neuronal classes starts at the time of their final mitotic divisions in the embryonic proliferative zones. This early cell determination continues during the migration of the newborn neurons across the widening cerebral wall, and it is in the cortical plate that they attain their final positions and establish species-specific cytoarchitectonic areas. Here, the development and evolutionary expansion of the neocortex is viewed in the context of the radial unit and protomap hypotheses. A broad spectrum of findings gave insight into the pathogenesis of cortical malformations and the biological bases for the evolution of the modern human neocortex. We examine the history and evidence behind the concept of early specification of neurons and provide the latest compendium of genes and signaling molecules involved in neuronal fate determination and specification.

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    • "Recently, Chen and colleagues investigated older human adult twins and demonstrated that genetic topography exhibited anterior–posterior and dorsal–ventral organizational gradients on a coarse level (Chen et al. 2011). This level of patterning by opposing gradients is supported by animal studies that used experimental inhibition or overexpression of specific genes (Bishop et al. 2000; O'Leary et al. 2007; Rakic et al. 2009). However, evidence of genetic influences on a finer scale has been sparse. "
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    ABSTRACT: Various brain structural and functional features such as cytoarchitecture, topographic mapping, gyral/sulcal anatomy, and anatomical and functional connectivity have been used in human brain parcellation. However, the fine-grained intrinsic genetic architecture of the cortex remains unknown. In the present study, we parcellated specific regions of the cortex into subregions based on genetic correlations (i.e., shared genetic influences) between the surface area of each pair of cortical locations within the seed region. The genetic correlations were estimated by comparing the correlations of the surface area between monozygotic and dizygotic twins using bivariate twin models. Our genetic subdivisions of diverse brain regions were reproducible across 2 independent datasets and corresponded closely to fine-grained functional specializations. Furthermore, subregional genetic correlation profiles were generally consistent with functional connectivity patterns. Our findings indicate that the magnitude of the genetic covariance in brain anatomy could be used to delineate the boundaries of functional subregions of the brain and may be of value in the next generation human brain atlas. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    Cerebral Cortex 08/2015; DOI:10.1093/cercor/bhv176 · 8.67 Impact Factor
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    • "Recent studies have revealed an unexpected degree of diversity in the intrinsic programs that determine neurotransmitter fate and cell type-specific connectivity of neurons derived from adult stem cells (Rakic et al., 2009; Ming and Song, 2011; Weinandy et al., 2011). It is an unanswered question whether GCs adopt the synaptic input patterns typical of the host circuit in which they integrate. "
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    ABSTRACT: New granule cell neurons (GCs) generated in the neonatal and adult subventricular zone (SVZ) have distinct patterns of input synapses in their dendritic domains. These synaptic input patterns determine the computations that the neurons eventually perform in the olfactory bulb. We observed that GCs generated earlier in postnatal life had acquired an 'adult' synaptic development only in one dendritic domain, and only later-born GCs showed an 'adult' synaptic development in both dendritic domains. It is unknown to what extent the distinct synaptic input patterns are already determined in SVZ progenitors and/or by the brain circuit into which neurons integrate. To distinguish these possibilities, we heterochronically transplanted retrovirally labeled SVZ progenitor cells. Once these transplanted progenitors, which mainly expressed Mash1, had differentiated into GCs, their glutamatergic input synapses were visualized by genetic tags. We observed that GCs derived from neonatal progenitors differentiating in the adult maintained their characteristic neonatal synapse densities. Grafting of adult SVZ progenitors to the neonate had a different outcome. These GCs formed synaptic densities that corresponded to neither adult nor neonatal patterns in two dendritic domains. In summary, progenitors in the neonatal and adult brain generate distinct GC populations and switch their fate to generate neurons with specific synaptic input patterns. Once they switch, adult progenitors require specific properties of the circuit to maintain their characteristic synaptic input patterns. Such determination of synaptic input patterns already at the progenitor-cell level may be exploited for brain repair to engineer neurons with defined wiring patterns.
    Development 12/2014; 142(2). DOI:10.1242/dev.110767 · 6.46 Impact Factor
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    • "Eph-ephrin interactions regulate a variety of neurodevelopmental processes, including axonal guidance, migration and apoptosis, in addition to proliferation (Drescher et al., 1997; Flanagan and Vanderhaeghen, 1998; Depaepe et al., 2005; Zimmer et al., 2008; North et al., 2009; Rudolph et al., 2010), and are crucial for establishing thalamocortical projections (Donoghue and Rakic, 1999; Šestan et al., 2001; Bolz et al., 2004). Despite intensive discussion as to whether cortical development is mainly regulated by intrinsic and/or extrinsic cues (Rakic, 1988, 1991; Dehay et al., 2001; Rakic et al., 2009; Zhou et al., 2010; Reillo et al., 2011), the thalamic influence on cortical progenitors and neurogenesis remains debated. Here, we provide further evidence for the extra-cortical regulation of cortical progenitors and hence the final output of neurons by thalamic afferents via the Eph/ephrin system. "
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    ABSTRACT: The phenotype of excitatory cerebral cortex neurons is specified at the progenitor level, orchestrated by various intrinsic and extrinsic factors. Here, we provide evidence for a subcortical contribution to cortical progenitor regulation by thalamic axons via ephrin A5-EphA4 interactions. Ephrin A5 is expressed by thalamic axons and represents a high-affinity ligand for EphA4 receptors detected in cortical precursors. Recombinant ephrin A5-Fc protein, as well as ephrin A ligand-expressing, thalamic axons affect the output of cortical progenitor division in vitro. Ephrin A5-deficient mice show an altered division mode of radial glial cells (RGCs) accompanied by increased numbers of intermediate progenitor cells (IPCs) and an elevated neuronal production for the deep cortical layers at E13.5. In turn, at E16.5 the pool of IPCs is diminished, accompanied by reduced rates of generated neurons destined for the upper cortical layers. This correlates with extended infragranular layers at the expense of superficial cortical layers in adult ephrin A5-deficient and EphA4-deficient mice. We suggest that ephrin A5 ligands imported by invading thalamic axons interact with EphA4-expressing RGCs, thereby contributing to the fine-tuning of IPC generation and thus the proper neuronal output for cortical layers. © 2015. Published by The Company of Biologists Ltd.
    Development 12/2014; 142(1). DOI:10.1242/dev.104927 · 6.46 Impact Factor
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