Molecular networks of the FOXP2 transcription factor in the brain

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Abstract

The discovery of the FOXP2 transcription factor, and its implication in a rare severe human speech and language disorder, has led to two decades of empirical studies focused on uncovering its roles in the brain using a range of in vitro and in vivo methods. Here, we discuss what we have learned about the regulation of FOXP2, its downstream effectors, and its modes of action as a transcription factor in brain development and function, providing an integrated overview of what is currently known about the critical molecular networks.

Abstract

FOXP2 was discovered 20 years ago to be required for human speech and language development. This review discusses molecular networks of FOXP2 regulation, downstream effectors, and how it acts as a transcription factor in brain development and function.

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Most cited references 176

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Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Ditte Demontis, Raymond K Walters, Joanna Martin … (2019)

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

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Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.

Jason D. Fontenot, Marc A Gavin, Alexander Rudensky (2003)

CD4+CD25+ regulatory T cells are essential for the active suppression of autoimmunity. Here we report that the forkhead transcription factor Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development. The lethal autoimmune syndrome observed in Foxp3-mutant scurfy mice and Foxp3-null mice results from a CD4+CD25+ regulatory T cell deficiency and not from a cell-intrinsic defect of CD4+CD25- T cells. CD4+CD25+ regulatory T cells rescue disease development and preferentially expand when transferred into neonatal Foxp3-deficient mice. Furthermore, ectopic expression of Foxp3 confers suppressor function on peripheral CD4+CD25- T cells. Thus, Foxp3 is a critical regulator of CD4+CD25+ regulatory T cell development and function.

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Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Brian O'Roak, Pelagia Deriziotis, Choli Lee … (2011)

Evidence for the etiology of autism spectrum disorders (ASD) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity 1,2 . We sequenced the exomes of 20 sporadic cases of ASD and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, of which 11 were protein-altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4/20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A, and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 mutation and provide functional support for a multihit model for disease risk 3 . Our results demonstrate that trio-based exome sequencing is a powerful approach for identifying novel candidate genes for ASD and suggest that de novo mutations may contribute substantially to the genetic risk for ASD.

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Author and article information

Contributors

Simon E Fisher:

ORCID: https://orcid.org/0000-0002-3132-1996

Simon.Fisher@mpi.nl

Journal

Journal ID (nlm-ta): EMBO Rep

Journal ID (iso-abbrev): EMBO Rep

Journal ID (doi): 10.1002/(ISSN)1469-3178

Journal ID (publisher-id): EMBR

Journal ID (hwp): embor

Title: EMBO Reports

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1469-221X

ISSN (Electronic): 1469-3178

Publication date (Electronic): 14 July 2021

Publication date (Print): 04 August 2021

Publication date PMC-release: 14 July 2021

Volume: 22

Issue: 8 ( doiID: 10.1002/embr.v22.8 )

Electronic Location Identifier: e52803

Affiliations

[ ¹ ] Language and Genetics Department Max Planck Institute for Psycholinguistics Nijmegen The Netherlands

[ ² ] International Max Planck Research School for Language Sciences Max Planck Institute for Psycholinguistics Nijmegen The Netherlands

[ ³ ] Donders Institute for Brain, Cognition and Behaviour Radboud University Nijmegen The Netherlands

Author notes

[*] [* ] Corresponding author. Tel: +31 24 3521441; E‐mail: Simon.Fisher@ 123456mpi.nl

Author information

Joery den Hoed https://orcid.org/0000-0001-6614-876X

Simon E Fisher https://orcid.org/0000-0002-3132-1996

Article

Publisher ID: EMBR202152803

DOI: 10.15252/embr.202152803

PMC ID: 8339667

PubMed ID: 34260143

SO-VID: 9692d837-1dc5-4479-9235-badf3db40cef

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 19 May 2021

Date received : 05 March 2021

Date accepted : 23 June 2021

Page count

Figures: 4, Tables: 0, Pages: 15, Words: 12936

Funding

Funded by: Max‐Planck‐Gesellschaft (MPG) , doi 10.13039/501100004189;

Custom metadata

source-schema-version-number 2.0

cover-date 04 August 2021

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:05.08.2021

ScienceOpen disciplines: Molecular biology

Keywords: foxp2,molecular network,neurodevelopment,speech disorder,transcription factor,chromatin, epigenetics, genomics & functional genomics,neuroscience

Data availability:

ScienceOpen disciplines: Molecular biology

Keywords: foxp2, molecular network, neurodevelopment, speech disorder, transcription factor, chromatin, epigenetics, genomics & functional genomics, neuroscience

Molecular networks of the FOXP2 transcription factor in the brain

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Most cited references 176

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

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