The Specification of Cortical Subcerebral Projection Neurons Depends on the Direct Repression of TBR1 by CTIP1/BCL11a

Cánovas, José Luis; Fa, Berndt; Sepúlveda, Hugo; Aguilar, Rodrigo; Veloso, Felipe A.; Montecino, Martín; Oliva, Carlos; Maass, Juan C.; Sierralta, Jimena; Kukuljan, Manuel

doi:10.1523/jneurosci.0169-15.2015

Cited by 56 publications

(54 citation statements)

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“…Hevner et al () also reported ER81 expression in corticospinal neurons, while Harb et al (2016) indicated that ER81 + cells are solely callosal projection neurons. Given that Ctip2 is expressed mostly in subcortical projection neurons, our ER81 + Ctip2 + cells in layer 5 of S1 may include corticospinal and corticocollicular neurons in line with the report by Arlotta et al (), while ER81 + Ctip2 ‐ cells may include callosal neurons (Canovas et al, ). In contrast to these reports, Dehorter et al () suggests that the majority of ER81 cells is interneurons, mostly expressing parvalbumin but also somatostatin, in layer 2/3 of mouse SCx.…”

Section: Discussionsupporting

confidence: 89%

Laminar specific gene expression reveals differences in postnatal laminar maturation in mouse auditory, visual, and somatosensory cortex

Chang¹,

Suzuki²,

Kawai³

2018

J of Comparative Neurology

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Proper formation of laminar structures in sensory cortexes is critical for sensory information processing. Previous studies suggested that the timing of neuronal migration and the laminar position of cortical neurons differ among sensory cortexes. How they differ during postnatal development has not been systematically investigated. Here, identifying laminas using transcription factors, we examined postnatal changes in neuronal density and distribution in presumptive primary auditory (ACx), visual (VCx), and somatosensory cortexes (SCx) in a strain of mice using immunofluorescence techniques. Development of laminar thickness and its cortical proportion differed among the sensory cortexes. Layers 2-4 defined by Cut-like homeobox 1 (Cux1)-expressing neurons were narrower, and layer 5 was wider in ACx compared to those in VCx or SCx, while Forkhead-box protein P2 (Foxp2)-defined layer 6 was wider in SCx than the other two sensory cortexes throughout postnatal development. Meanwhile, thalamocortical input layers identified by Cux1-expressing neurons formed later in ACx than in the other two cortical regions. The cell densities of ETS-related protein 81-expressing neurons increased in both lower and upper layers but at distinct timing, while those of COUP-TF-interacting protein 2 expressing neurons in the lower layers changed bidirectionally (i.e., increased or decreased) both in layer- and cortical region-specific manners. Foxp2-expressing cells in layer 6 distributed differently and declined at different timing among the sensory cortexes. Overall, we demonstrate that the maturational timing of lamina differs among the sensory cortexes and that postnatal age-dependent changes in neuronal distribution are unique to each of the sensory cortexes.

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Section: Discussionsupporting

confidence: 89%

Laminar specific gene expression reveals differences in postnatal laminar maturation in mouse auditory, visual, and somatosensory cortex

Chang¹,

Suzuki²,

Kawai³

2018

J of Comparative Neurology

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“…Our model of Ctip1 function is at odds with that of Cánovas et al (Cánovas et al, 2015), who recently proposed that CTIP1 is extensively co-expressed with CTIP2 and is a positive control over SCPN development through repression of TBR1. In direct contrast, we demonstrate that expression of TBR1 and other characteristic CThPN genes is reduced in the absence of Ctip1 (Figure 3G–L, Figure 4M–O), and that expression of CTIP2 is increased (Figure 3A–B), leading to more early-born neurons becoming SCPN (Figure 4A–F).…”

Section: Discussioncontrasting

confidence: 80%

Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers

et al. 2016

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SUMMARY The molecular linkage between neocortical projection neuron subtype and area development, which enables the establishment of functional areas by projection neuron populations appropriate for specific sensory and motor functions, is poorly understood. Here, we report that Ctip1 controls precision of neocortical development by regulating subtype identity in deep-layer projection neurons. Ctip1 is expressed by postmitotic callosal and corticothalamic projection neurons, but is excluded over embryonic development from corticospinal motor neurons, which instead express its close relative, Ctip2. Loss of Ctip1 function results in a striking bias in favor of subcerebral projection neuron development in sensory cortex at the expense of corticothalamic and deep-layer callosal development, while misexpression of Ctip1 in vivo represses subcerebral gene expression and projections. As we report in a paired paper, Ctip1 also controls acquisition of sensory area identity. Therefore, Ctip1 couples subtype and area specification, enabling specific functional areas to organize precise ratios of appropriate output projections.

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“…Mutations in TBR1 are associated with intellectual disability and ASD, and functional implications will likely impact its activity as a transcriptional regulator, its cellular localization or its interaction with co-regulators. Complex interactions of several genes with Tbr1 determine the corticothalamic projection of layer VI neurons, callosal projection of neurons in the cortical superficial layers [335] and subcortical projection of layer V neurons [50, 142, 232]. Tbr1 in turn regulates the expression of rostrocaudal and layer-specific markers in the cerebral cortex, the former being partly through activation of the autism gene AUTS2 [28].…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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The Specification of Cortical Subcerebral Projection Neurons Depends on the Direct Repression of TBR1 by CTIP1/BCL11a

Cited by 56 publications

References 56 publications

Laminar specific gene expression reveals differences in postnatal laminar maturation in mouse auditory, visual, and somatosensory cortex

Laminar specific gene expression reveals differences in postnatal laminar maturation in mouse auditory, visual, and somatosensory cortex

Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers

Autism spectrum disorder: neuropathology and animal models

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