ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c

Gaia Colasante, Jacqueline C. Simonet, Raffaele Calogero, Stefania Crispi, Alessandro Sessa, Ginam Cho, Jeffrey A. Golden, Vania Broccoli

Research output: Contribution to journalArticle

Abstract

Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx â '/Y mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.

Original languageEnglish
Pages (from-to)322-335
Number of pages14
JournalCerebral Cortex
Volume25
Issue number2
DOIs
Publication statusPublished - 2015

Fingerprint

Homeobox Genes
Stem Cells
Neurons
Cell Cycle
Brain
Intellectual Disability
Cerebral Cortex
Epilepsy
Cell Proliferation
Mutation

Keywords

  • cell cycle
  • forebrain development
  • neurodevelopmental disorders
  • neurogenesis
  • TBR2

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cognitive Neuroscience

Cite this

ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c. / Colasante, Gaia; Simonet, Jacqueline C.; Calogero, Raffaele; Crispi, Stefania; Sessa, Alessandro; Cho, Ginam; Golden, Jeffrey A.; Broccoli, Vania.

In: Cerebral Cortex, Vol. 25, No. 2, 2015, p. 322-335.

Research output: Contribution to journalArticle

Colasante, G, Simonet, JC, Calogero, R, Crispi, S, Sessa, A, Cho, G, Golden, JA & Broccoli, V 2015, 'ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c', Cerebral Cortex, vol. 25, no. 2, pp. 322-335. https://doi.org/10.1093/cercor/bht222
Colasante, Gaia ; Simonet, Jacqueline C. ; Calogero, Raffaele ; Crispi, Stefania ; Sessa, Alessandro ; Cho, Ginam ; Golden, Jeffrey A. ; Broccoli, Vania. / ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c. In: Cerebral Cortex. 2015 ; Vol. 25, No. 2. pp. 322-335.
@article{6a6966ad21f94b1da9c56d7814a0569a,
title = "ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c",
abstract = "Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx {\^a} '/Y mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.",
keywords = "cell cycle, forebrain development, neurodevelopmental disorders, neurogenesis, TBR2",
author = "Gaia Colasante and Simonet, {Jacqueline C.} and Raffaele Calogero and Stefania Crispi and Alessandro Sessa and Ginam Cho and Golden, {Jeffrey A.} and Vania Broccoli",
year = "2015",
doi = "10.1093/cercor/bht222",
language = "English",
volume = "25",
pages = "322--335",
journal = "Cerebral Cortex",
issn = "1047-3211",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c

AU - Colasante, Gaia

AU - Simonet, Jacqueline C.

AU - Calogero, Raffaele

AU - Crispi, Stefania

AU - Sessa, Alessandro

AU - Cho, Ginam

AU - Golden, Jeffrey A.

AU - Broccoli, Vania

PY - 2015

Y1 - 2015

N2 - Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx â '/Y mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.

AB - Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx â '/Y mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.

KW - cell cycle

KW - forebrain development

KW - neurodevelopmental disorders

KW - neurogenesis

KW - TBR2

UR - http://www.scopus.com/inward/record.url?scp=84924977803&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924977803&partnerID=8YFLogxK

U2 - 10.1093/cercor/bht222

DO - 10.1093/cercor/bht222

M3 - Article

C2 - 23968833

AN - SCOPUS:84924977803

VL - 25

SP - 322

EP - 335

JO - Cerebral Cortex

JF - Cerebral Cortex

SN - 1047-3211

IS - 2

ER -