A network of genetic repression and derepression specifies projection fates in the developing neocortex

Department of Biology, Stanford University, Stanford, CA 94305.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2012; 109(47). DOI: 10.1073/pnas.1216793109
Source: PubMed


Neurons within each layer in the mammalian cortex have stereotypic projections. Four genes-Fezf2, Ctip2, Tbr1, and Satb2-regulate these projection identities. These genes also interact with each other, and it is unclear how these interactions shape the final projection identity. Here we show, by generating double mutants of Fezf2, Ctip2, and Satb2, that cortical neurons deploy a complex genetic switch that uses mutual repression to produce subcortical or callosal projections. We discovered that Tbr1, EphA4, and Unc5H3 are critical downstream targets of Satb2 in callosal fate specification. This represents a unique role for Tbr1, implicated previously in specifying corticothalamic projections. We further show that Tbr1 expression is dually regulated by Satb2 and Ctip2 in layers 2-5. Finally, we show that Satb2 and Fezf2 regulate two disease-related genes, Auts2 (Autistic Susceptibility Gene2) and Bhlhb5 (mutated in Hereditary Spastic Paraplegia), providing a molecular handle to investigate circuit disorders in neurodevelopmental diseases.

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Available from: Susan K McConnell, Jan 14, 2015
    • "TBR1 is highly expressed in deep layers of the cerebral cortex, which have been suggested to participate in ASD pathology (Willsey et al. 2013). TBR1 target genes include multiple other autism risk factors (Chuang et al. 2015), and in particular TBR1 activates AUTS2 (Bedogni et al. 2010a; Srinivasan et al. 2012). Pathogenic de novo truncating and missense mutations disrupted multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression (Deriziotis et al. 2014). "
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    ABSTRACT: Autism Spectrum Disorders (ASD) encompass a group of neurodevelopmental diseases that demonstrate strong heritability, however the inheritance is not simple and many genes have been associated with these disorders. ASD is regarded as a neurodevelopmental disorder, and abnormalities at different developmental stages are part of the disease etiology. This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 10/2015; DOI:10.1111/jnc.13403 · 4.28 Impact Factor
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    • "The molecular logic underlying this DL neuron fate bias of progenitors was again uncovered through Foxg1 downstream transcriptome analysis. Of the layer transcription factors, Tbr1, which is expressed in the majority of early-born neurons (Hevner et al., 2001) and establish the corticothalamic projection neuron identity within the layer-subtype transcriptional network (Han et al., 2011; McKenna et al., 2011; Srinivasan et al., 2012), exhibited a significant downregulated response to Foxg1 induction. A reporter assay revealed that this repression was mediated through a 4-kb Tbr1 promoter region consisting of multiple conserved Foxg1 binding sequences. "
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    Frontiers in Neuroscience 08/2015; 9:274. DOI:10.3389/fnins.2015.00274 · 3.66 Impact Factor
    • "The increased number of Bcl11b-positive neurons might be caused by compensatory upregulation of this closely related gene. Upregulation of Bcl11b could be responsible for Tbr1 repression in the deep cortical layers of the Bcl11a mutants; such a mechanism was previously observed in Satb2 mutants that show upregulation of Bcl11b as well (Srinivasan et al., 2012). At P2, we did not detect changes in the distribution of deep-layer neurons within the CP. "
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    ABSTRACT: During neocortical development, neurons undergo polarization, oriented migration, and layer-type-specific differentiation. The transcriptional programs underlying these processes are not completely understood. Here, we show that the transcription factor Bcl11a regulates polarity and migration of upper layer neurons. Bcl11a-deficient late-born neurons fail to correctly switch from multipolar to bipolar morphology, resulting in impaired radial migration. We show that the expression of Sema3c is increased in migrating Bcl11a-deficient neurons and that Bcl11a is a direct negative regulator of Sema3c transcription. In vivo gain-of-function and rescue experiments demonstrate that Sema3c is a major downstream effector of Bcl11a required for the cell polarity switch and for the migration of upper layer neurons. Our data uncover a novel Bcl11a/Sema3c-dependent regulatory pathway used by migrating cortical neurons. Copyright © 2015 Elsevier Inc. All rights reserved.
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