Satb2 Is a Postmitotic Determinant for Upper-Layer Neuron Specification in the Neocortex

Britanova, Olga V.; Romero, Camino de Juan; Cheung, Ankie Tan; Kwan, Kenneth Y.; Schwark, Manuela; György, Andrea; Vogel, Tanja; Akopov, S. B.; Mitkovski, Mišo; Ägoston, Dénes V.; Šestan, Nenad; Molnár, Zoltán; Tarabykin, Victor

doi:10.1016/j.neuron.2007.12.028

Cited by 616 publications

(795 citation statements)

References 36 publications

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“…indicating that precise levels of CSMN-specific genes are a fundamental requisite for correct differentiation of corticofugal neurons. Finally, because COUP-TFI and Fezf2 are both expressed in postmitotic neurons, it is possible that abnormal differentiation of CSMN and corticothalamic neurons in the absence of COUP-TFI occurs at a postmitotic level, as recently shown for other cortical transcriptional regulators (8,30,31,32).…”

Section: Coup-tfi Is a Negative Regulator Of A Genetic Csmn Differentmentioning

confidence: 84%

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

Tomassy

Leonibus

Jabaudon

et al. 2010

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

121

130

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Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise.arealization | subcerebral projection neurons | neocortex development | corticofugal neurons | nuclear receptor | behavior T he mammalian cerebral cortex, responsible for fine motor control and sensorimotor integration, is subdivided into functionally distinct areas that control motor functions and process distinct sensory modalities (1). Individual areas are distinguished by their cytoarchitecture, connectivity, physiology, and patterns of gene expression (2, 3). Each area is radially divided into six layers, and each layer consists of a variety of populations of neurons with distinctive morphologies, connectivity, and developmental programs of gene expression (4-9). In particular, layers VI and V contain corticofugal neurons, which send their axons to deep brain structures, such as the thalamus (corticothalamic neurons), the striatum (corticostriatal neurons), pons (corticopontine neurons), tectum (corticotectal neurons), and spinal cord (corticospinal motor neurons, CSMN) (7).The fate of neurons and laminar cytoarchitecture in each specific area determines their function: the adult primary motor cortex contains a large number of CSMN and has a thick layer V; the primary somatosensory area is characterized by a thick layer IV, where the neurons that receive relayed sensory inputs are located (10). The area-specific differences in neuronal fate and cytoarchitecture have been thought to result from late postmitotic events, e.g. selective postnatal pruning of axons (11), and premitotic events, such as the timing, rate, and duration of proliferation of precursors producing distinct projection neuron subtypes (12-16). As a striking illustration of such processes, CSMN are generated at a higher rate in the developing motor cortex than in sensory areas in mice (12), but the molecular mechanisms that control this area-specific differential production of CSMN are not known. The transcription factor COUP-TFI is particularly interestin...

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Section: Coup-tfi Is a Negative Regulator Of A Genetic Csmn Differentmentioning

confidence: 84%

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

Tomassy

Leonibus

Jabaudon

et al. 2010

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

121

130

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“…Notable among the genes significantly up-regulated at E12.5 in the Ezh2-null cortex are a large set of transcription factors and other genes specifically expressed in differentiating cortical neurons (Fig. 2C), such as Neurod6, Mef2c, Myt1l, and Bcl11b (expressed in all cortical neurons) and genes specifically expressed in either early-born or later-born cortical neuron types, including corticothalamic and callosal projection neurons (25): Reelin (marginal zone neurons); Moxd1 and Tmem163 (subplate neurons); Tbr1 and Foxp2 (layer 6 neurons), Foxo1 and Pou3f1/ SCIP (layer 5 neurons); Lmo4 and Foxp1 (callosal projection neurons of layers 3-5); Bhlhb5/Bhlhe22 (neurons in layers 2-5); Ror-beta (layer 4 neurons); and Satb2 (neurons in layers 2-4) (25)(26)(27)(28)(29)(30)(31). The increase in layer-specific neuronal gene expression at this early point in cortical development suggested that cortical development may be more advanced in the Ezh2-null cortex than in control littermates.…”

Section: Loss Of Prc2 Function Results In Up-regulated Gene Expressiomentioning

confidence: 99%

Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex

Pereira

Sansom

Smith

et al. 2010

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

416

433

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Multipotent progenitor cells of the cerebral cortex balance selfrenewal and differentiation to produce complex neural lineages in a fixed temporal order in a cell-autonomous manner. We studied the role of the polycomb epigenetic system, a chromatin-based repressive mechanism, in controlling cortical progenitor cell selfrenewal and differentiation. We found that the histone methyltransferase of polycomb repressive complex 2 (PCR2), enhancer of Zeste homolog 2 (Ezh2), is essential for controlling the rate at which development progresses within cortical progenitor cell lineages. Loss of function of Ezh2 removes the repressive mark of trimethylated histone H3 at lysine 27 (H3K27me3) in cortical progenitor cells and also prevents its establishment in postmitotic neurons. Removal of this repressive chromatin modification results in marked up-regulation in gene expression, the consequence of which is a shift in the balance between self-renewal and differentiation toward differentiation, both directly to neurons and indirectly via basal progenitor cell genesis. Although the temporal order of neurogenesis and gliogenesis are broadly conserved under these conditions, the timing of neurogenesis, the relative numbers of different cell types, and the switch to gliogenesis are all altered, narrowing the neurogenic period for progenitor cells and reducing their neuronal output. As a consequence, the timing of cortical development is altered significantly after loss of PRC2 function.development | epigenetics | stem cells | chromatin

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“…Pyramidal neurons can be subdivided into numerous subtypes, defined in vivo by a repertoire of molecular markers, identifying distinct layer-specific neuronal populations 7,[22][23][24] . To examine the diversity of the neuronal repertoire derived from ESCs in DDM plus cyclopamine, we studied the expression of a large set of layer-specific markers corresponding to the major subtypes of cortical neurons generated in vivo in the mouse (Fig.…”

Section: Sequential Cortical Neurogenesis From Escsmentioning

confidence: 99%

An intrinsic mechanism of corticogenesis from embryonic stem cells

Gaspard

Bouschet

Hourez

et al. 2008

Nature

584

634

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The cerebral cortex develops through the coordinated generation of dozens of neuronal subtypes, but the mechanisms involved remain unclear. Here we show that mouse embryonic stem cells, cultured without any morphogen but in the presence of a sonic hedgehog inhibitor, recapitulate in vitro the major milestones of cortical development, leading to the sequential generation of a diverse repertoire of neurons that display most salient features of genuine cortical pyramidal neurons. When grafted into the cerebral cortex, these neurons develop patterns of axonal projections corresponding to a wide range of cortical layers, but also to highly specific cortical areas, in particular visual and limbic areas, thereby demonstrating that the identity of a cortical area can be specified without any influence from the brain. The discovery of intrinsic corticogenesis sheds new light on the mechanisms of neuronal specification, and opens new avenues for the modelling and treatment of brain diseases.

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Satb2 Is a Postmitotic Determinant for Upper-Layer Neuron Specification in the Neocortex

Cited by 616 publications

References 36 publications

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex

An intrinsic mechanism of corticogenesis from embryonic stem cells

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