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Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c

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.

ORGANISM(S): Mus musculus

PROVIDER: GSE52827 | GEO | 2015/06/17

SECONDARY ACCESSION(S): PRJNA230251

REPOSITORIES: GEO

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Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c

Project description: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. Neocortex tissue from three control (Bcl11a+/+) and three Bcl11a mutants (Bcl11aΔflox/Δflox) embryos was collected at E14.5. Total RNA was isolated from each sample separately using the RNeasy kit (Qiagen). The isolated ENA was inspected for integrity and purity using an Agilent Bioanalyzer and a NanoDrop spectrophotometer, respectively. Microarray analyses were performed using 200 ng total RNA as starting material and 5.5 µg ssDNA per hybridization in a GeneChip Fluidics Station 450 (Affymetrix). The total RNAs were amplified and labeled following the Whole Transcript (WT) Sense Target Labeling Assay (Affymetrix). Labeled ssDNA was hybridized to Mouse Gene 1.0 ST Affymetrix GeneChip arrays (Affymetrix). The chips were scanned with a GeneChip Scanner 3000 (Affymetrix) and subsequent images analyzed using Affymetrix Expression Console Software (Affymetrix). A transcriptome analysis was performed using BRB-ArrayTools developed by Dr. Richard Simon and BRB-ArrayTools Development Team (http://linus.nci.nih.gov/BRB-ArrayTools.html).

2015-06-17 | E-GEOD-52827 | biostudies-arrayexpress

Mus musculus

Project description:Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c

| PRJNA230251 | ENA

Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6-dependent pathway II

Project description:Developmental neuron death plays a pivotal role in refining organization and wiring during neocortex formation. Aberrant regulation of this process results in neurodevelopmental disorders including impaired learning and memory. Underlying molecular pathways are incompletely determined. Loss of Bcl11a in cortical projection neurons induces pronounced cell death in upper-layer cortical projection neurons during postnatal corticogenesis. We used this genetic model to explore genetic mechanisms by which developmental neuron death is controlled. Unexpectedly, we found Bcl6, previously shown to be involved in transition of cortical neurons from progenitor to postmitotic differentiation state to provide a major check point regulating neuron survival during late cortical development. We show that Bcl11a is a direct transcriptional regulator of Bcl6. Deletion of Bcl6 exerts death of cortical projection neurons. In turn, reintroduction of Bcl6 into Bcl11a mutants prevents induction of cell death in these neurons. Together, our data identify a novel Bcl11a/Bcl6-dependent molecular pathway in regulation of developmental cell death during corticogenesis.

2022-06-24 | GSE185288 | GEO

Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6-dependent pathway I

2022-06-24 | GSE185287 | GEO

FACS microarray analysis of radially migrating cortical neurons

Project description:During the developmental formation of 6-layered neocortical structure of mammalian cerebral cortex, newborn excitatory neurons depart the ventricular zone and migrate toward the pial surface. At a middle stage of cortical development, newly differentiated postmitotic neurons adopt a multipolar shape (MP), and exhibit a random non-directional migration in the intermediate zone (multipolar migration). When these neurons pass through the subplate layer (SP), they convert to a bipolar shape (BP), and then migrate radially toward the pial surface (locomotion). In order to elucidate the molecular mechanisms of such neuronal migration, we performed a gene expression profiling of newborn excitatory neurons during their migration processes. After in utero electroporation of GFP expressing plasmid into E14 mouse cortex, GFP-positive cells were collected using FACS sorting method after one, two, or three days of electroporation. RNAs of collected GFP-positive cells at each day were purified and applied to microarray analyses. gene-ontology and pathway analyses revealed that genes encoding synaptic proteins, receptors and ECM-related proteins were up-regulated as the migration proceeds. On the other hand, genes encoding cell cycle regulation and immune-related proteins were down-regulated. We will discuss the relationship between the migration mode and the transition of the gene expression.

2017-08-23 | GSE102911 | GEO

Upper cortical layer-driven network impairment in schizophrenia

Project description:Schizophrenia is one of the most wide-spread and complex mental disorders. To characterize the impact of schizophrenia, we performed single nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. Additionally, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most dramatic - in upper layer GABAergic neurons, including downregulation in energy metabolism and upregulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Finally, Visium spatial transcriptomics further corroborated upper layer neuron vulnerability in schizophrenia. Overall, our results point towards general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology. Study is available on bioRxiv (https://doi.org/10.1101/2020.11.17.386458) and in upcoming publication.

| EGAS00001006495 | EGA

Cell-intrinsic regulation of interneuron migration controls cortical neurogenesis

Project description:Interneurons navigate along multiple tangential paths to settle into appropriate cortical layer. They undergo saltatory migration, which is paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. However, it remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes deglutamylation, is a pivotal regulator of pausing of cortical interneurons. Moreover, we show that pausing during migration controls the flow of interneurons invading the cortex by generating heterogeinity in movement at the population level. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also secondarily impairs the generation of age-matched upper layer projection neurons.

2018-02-14 | PXD006397 | Pride

GABAA receptors and mother-derived taurine regulate neural progenitor cells specification in the mouse developing cortex

Project description:The precise temporal regulation of the cellular properties of neural progenitor cells (NPCs) is essential for the histogenesis of the cerebral cortex. Neuroepithelial cells, the primary NPCs, transit to radial glia with astroglial properties. To coincide with this transition, NPCs start to differentiate into neurons, undergoing a switch from symmetric to asymmetric cell division. After the onset of neurogenesis, NPCs produce layer-specific neurons in a defined order. Here, we show that GABAA receptors and taurine are involved in this regulatory mechanism. Fetal exposure to GABAA blockers suppressed the transition to radial glia, the switch to asymmetric division and the differentiation into upper-layer neurons. Fetal exposure to GABAA positive modulators caused the opposite effects. Ca2+ imaging studies showed that NPCs principally responded to taurine, but not GABA, which is derived principally from mothers, before E13 via picrotoxin-sensitive receptors. Fetal exposure to GABAA receptor modulators resulted in considerable alterations in offspring behavior.

2016-10-31 | GSE77648 | GEO

Heterogeneous fates of simultaneously-born neurons during early corticogenesis

Project description:We labelled isochronic cohorts of mouse cortical neurons and analyzed their contribution to the diversity of cortical neurons. We find that early born neurons contribute to a large diversity of cortical neuron subtypes, asa also confirmed by the transcsriptomic analysis of E13.5 born neurons through Patchseq. Ultimately we identify eaarly differentiation of early born neurons as the instance characterized by the highest tranascriptomical variability which intermingles deep layer identity genes with upper layer specific ones.

2022-12-18 | GSE142601 | GEO

Single cell RNA-sequencing of 75-day old human H1 and H9 embryonic stem cell-derived cerebral organoids

Project description:The scRNA-seq analysis of 75 day old human cerebral organoids grown at the air-liquid interface (ALI-COs) reveals six well-defined major clusters. Cell-type and maturity markers define a (1) distinct population of deep layer subcortical projection neurons, (2) upper layer intracortical (callosal) projection neurons and intermediate progenitors, (3) ventricular and subventricular zone radial glial cells, (4) more mature upper and deep layer neurons, (5) interneurons and (6) actively dividing cells with intermediate progenitor and radial glia markers. In addition, the gene expression profile of these clusters corresponds with their expected functional characteristics appropriate to their maturity. Altogether, our data reflect a full repertoire of cortical neuronal and progenitor identities corresponding with the stages of cortical development in age-matched fetal brains.

2019-02-28 | GSE124174 | GEO

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