Functional and Evolutionary Insights into Human Brain Development through Global Transcriptome Analysis

Johnson, Matthew B.; Kawasawa, Yuka Imamura; Mason, Christopher E.; Krsnik, Željka; Coppola, Giovanni; Bogdanović, Darko; Geschwind, Daniel H.; Mane, Shrikant; State, Matthew W.; Šestan, Nenad

doi:10.1016/j.neuron.2009.03.027

Cited by 557 publications

(560 citation statements)

References 79 publications

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“…It also suggests that the regulatory pathways that establish this pattern are well conserved. Consistent with this, the prenatal neocortical expression patterns of Fezf2, Tbr1, and Sox5 are similar in different mammals, including humans (15,26,27). Therefore, TBR1-mediated down-regulation of Fezf2 in L6 is most likely a conserved mechanism for restricting the laminar origin of the CS tract to L5.…”

Section: Discussionsupporting

confidence: 65%

TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract

Han

Kwan

Shim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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188

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The corticospinal (CS) tract is involved in controlling discrete voluntary skilled movements in mammals. The CS tract arises exclusively from layer (L) 5 projection neurons of the cerebral cortex, and its formation requires L5 activity of Fezf2 (Fezl, Zfp312). How this L5-specific pattern of Fezf2 expression and CS axonal connectivity is established with such remarkable fidelity had remained elusive. Here we show that the transcription factor TBR1 directly binds the Fezf2 locus and represses its activity in L6 corticothalamic projection neurons to restrict the origin of the CS tract to L5. In Tbr1 null mutants, CS axons ectopically originate from L6 neurons in a Fezf2-dependent manner. Consistently, misexpression of Tbr1 in L5 CS neurons suppresses Fezf2 expression and effectively abolishes the CS tract. Taken together, our findings show that TBR1 is a direct transcriptional repressor of Fezf2 and a negative regulator of CS tract formation that restricts the laminar origin of CS axons specifically to L5.neocortex | pyramidal neuron | axon guidance | transcriptional repression S patial specificity of axonal connections is one of the most important prerequisites for normal development (1-3). In mammals, this is especially crucial for axons of the corticospinal (CS) system (4-7). Development of the CS tract is an intricate process that involves the molecular specification of CS neurons and axon pathfinding. All long-range subcortical axons projecting to the brainstem and spinal cord, including those that form the CS tract, originate exclusively from layer (L) 5 projection (pyramidal) neurons of the cerebral cortex (8-11). Projection neurons in other cortical layers give rise to axons that project within the cortex (L2-4) or to the thalamus (L6). How this highly conserved laminar pattern of projections is formed with such perfect accuracy remains elusive.Previous work revealed that the transcription factor FEZF2 (FEZL, ZFP312) is highly enriched in L5 CS neurons and is critical to the development of the CS tract (12-14). Inactivation of Fezf2 disrupts formation of the CS tract (12-14), whereas misexpression of Fezf2 in upper layer projection neurons induces ectopic subcortical projections (13). These findings indicate that Fezf2 transcription is tightly regulated during development, and that the integrity of normal Fezf2 expression is critical to proper development of the CS tract. Interestingly, Fezf2 is transiently expressed in L6 neurons during early embryonic development, where its transcription is directly repressed by SOX5, thereby establishing a high-in-L5, low-in-L6 postnatal pattern (15, 16). Paradoxically, in Sox5 null mutants, the number of axon projections reaching the brainstem and spinal cord is severely reduced despite increased cortical Fezf2 expression (15). This suggests that Sox5 is required for the formation of these connections independent of its regulation of Fezf2. Furthermore, SOX5 is normally expressed in L5 Fezf2-expressing CS neurons (15). Therefore, the down-regulation of Fezf2 in L6 neu...

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Section: Discussionsupporting

confidence: 65%

TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract

Han

Kwan

Shim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

188

212

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“…While differential gene expression is most pronounced during prenatal development [39] and between subcortical structures [40], substantial spatial variation has also been described within the adult human cerebral cortex [40][41][42][43].…”

Section: Glossarymentioning

confidence: 99%

Large-Scale Gradients in Human Cortical Organization

Huntenburg

Bazin

Margulies

2018

Trends in Cognitive Sciences

717

703

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Recent advances in mapping cortical areas in the human brain provide a basis for investigating the significance of their spatial arrangement. Here we describe a dominant gradient in cortical features that spans between sensorimotor and transmodal areas. We propose that this gradient constitutes a core organizing axis of the human cerebral cortex, and describe an intrinsic coordinate system on its basis. Studying the cortex with respect to these intrinsic dimensions can inform our understanding of how the spectrum of cortical function emerges from structural constraints. The Significance of Cortical LocationFor more than a century, neuroscientists have studied the cerebral cortex by delineating individual cortical areas (see Glossary) and mapping their function [1]. This agenda has substantially advanced in recent years, as automated parcellation methods improve and data sets of unprecedented size and quality become available [2][3][4]. Nevertheless, our understanding of how the complex structure of the cerebral cortex emerges and gives rise to its elaborate functions remains fragmentary. To complement the description of individual cortical areas, we propose an inquiry into the significance of their spatial arrangement, asking the basic question: Why are cortical areas located where they are?Early formulations of this question date to theories from classical neuroanatomy [1,[5][6][7]. They state that the spatial layout of cortical areas is not arbitrary, but a consequence of developmental mechanisms, shaped through evolutionary selection. The location of an area among its neighbors thus provides insight into its microstructural characteristics [6], its connections to other parts of the brain [7], and eventually its position in global processing hierarchies [8]. Consider, for example, the well-researched visual system of the macaque monkey [9,10]. Along the visual hierarchy, low-level visual features are increasingly abstracted and integrated with information from other systems. Traditionally, areas are ordered based on their degree of microstructural differentiation, and the classification of their connections as feedforward or feedback [11]. The framework we advocate emphasizes that an area's position in the visual processing hierarchy -and thus many of its microstructural and connectional features -is strongly related to its distance from the primary visual area [12,13].More generally, we propose that the spatial arrangement of areas along a global gradient between sensorimotor and transmodal regions is a key feature of human cortical organization. A gradient is an axis of variance in cortical features, along which areas fall in a spatially continuous order. Areas that resemble each other with respect to the feature of interest occupy similar positions along the gradient. As we will point out, there is a strong relationship between the similarity of two areas -that is, their relative position along the gradient -and their relative position along the cortical surface. This important role of cortical location pro...

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“…human embryonic stem cell | embryo | differentiation | cortical layer E merging data highlight the complexity and dynamic nature of gene expression in the central nervous system (CNS) and the divergence between human and other mammalian species, which is especially pronounced in the developing brain (1)(2)(3)(4). Exploring such differences may reveal the genetic underpinnings of the larger size and complex architecture of the human brain and elucidate the molecular and cellular substrates of higher cognitive functions, as well as of our vulnerability to neurodevelopmental and neurodegenerative disorders.…”

mentioning

confidence: 99%

Modeling human cortical development in vitro using induced pluripotent stem cells

Mariani

Simonini

Palejev

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

450

369

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Human induced pluripotent stem cells (hiPSCs) are emerging as a tool for understanding human brain development at cellular, molecular, and genomic levels. Here we show that hiPSCs grown in suspension in the presence of rostral neuralizing factors can generate 3D structures containing polarized radial glia, intermediate progenitors, and a spectrum of layer-specific cortical neurons reminiscent of their organization in vivo. The hiPSC-derived multilayered structures express a gene expression profile typical of the embryonic telencephalon but not that of other CNS regions. Their transcriptome is highly enriched in transcription factors controlling the specification, growth, and patterning of the dorsal telencephalon and displays highest correlation with that of the early human cerebral cortical wall at 8-10 wk after conception. Thus, hiPSC are capable of enacting a transcriptional program specifying human telencephalic (pallial) development. This model will allow the study of human brain development as well as disorders of the human cerebral cortex.human embryonic stem cell | embryo | differentiation | cortical layer E merging data highlight the complexity and dynamic nature of gene expression in the central nervous system (CNS) and the divergence between human and other mammalian species, which is especially pronounced in the developing brain (1-4). Exploring such differences may reveal the genetic underpinnings of the larger size and complex architecture of the human brain and elucidate the molecular and cellular substrates of higher cognitive functions, as well as of our vulnerability to neurodevelopmental and neurodegenerative disorders. To understand the genetic programs that drive cell specification and differentiation in the human brain, it is important to develop model systems that recapitulate dynamic aspects of neural development, in addition to making inferences from commonly used models of lower mammalian species.Recapitulating human neural development in vitro using human induced pluripotent stem cells (hiPSCs) can provide our first understanding of how genetic variation and disease-causing mutations influence neural development. Human iPSCs generated from reprogrammed cells can be differentiated into any tissue, including the CNS, while maintaining the genetic background of the individual of origin. These critical features have been exploited to model monogenic forms of neurodevelopmental disorders, such as Rett and Timothy syndromes, and even psychiatric disorders with complex inheritance, such as schizophrenia (5-7). The brain and spinal cord develop according to distinct differentiation programs from the earliest stages of CNS development (i.e., at the progenitor stage during gastrulation) (8, 9). Regional differences in gene expression within stem and progenitor cells appear at the onset of the formation of both mouse (10, 11) and human CNS, as shown by recent studies of the human transcriptome using postmortem tissue (4).Neural cells are thought to differentiate by "default" into an anterior, for...

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Functional and Evolutionary Insights into Human Brain Development through Global Transcriptome Analysis

Cited by 557 publications

References 79 publications

TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract

TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract

Large-Scale Gradients in Human Cortical Organization

Modeling human cortical development in vitro using induced pluripotent stem cells

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