FOXP2 exhibits neuron class specific expression, but is not required for multiple aspects of cortical histogenesis
Abstract
The expression patterns of the transcription factor FOXP2 in the developing mammalian forebrain have been described, and some studies have tested the role of this protein in the development and function of specific forebrain circuits by diverse methods and in multiple species. Clinically, mutations in FOXP2 are associated with severe developmental speech disturbances, and molecular studies indicate that impairment of Foxp2 may lead to dysregulation of genes involved in forebrain histogenesis. Here, anatomical and molecular phenotypes of the cortical neuron populations that express FOXP2 were characterized in mice. Additionally, Foxp2 was removed from the developing mouse cortex at different prenatal ages using two Cre-recombinase driver lines. Detailed molecular and circuit analyses were undertaken to identify potential disruptions of development. Surprisingly, the results demonstrate that Foxp2 function is not required for many functions that it has been proposed to regulate, and therefore plays a more limited role in cortical development than previously thought.
Data availability
All numbers relating to quantitative experiments have been uploaded to Dryad. https://dx.doi.org/10.5061/dryad.6hd7bf7
-
Data from: FOXP2 exhibits neuron class specific expression, but is not required for multiple aspects of cortical histogenesisDryad Digital Repository, 10.5061/dryad.6hd7bf7.
Article and author information
Author details
Funding
National Institute of Mental Health (MH067842)
- Ryan J Kast
- Alexandra L Lanjewar
- Colton D Smith
- Pat Levitt
Children's Hospital Los Angeles
- Ryan J Kast
Simms/Mann Institute and Foundation
- Pat Levitt
National Institutes of Health (T32GM113859)
- Alexandra L Lanjewar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Constance L Cepko, Harvard Medical School, United States
Ethics
Animal experimentation: All animal procedures used in this study were in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Institutional Animal Care and Use Committee at Children's Hospital Los Angeles (Protocol #374-15).
Version history
- Received: September 14, 2018
- Accepted: May 14, 2019
- Accepted Manuscript published: May 17, 2019 (version 1)
- Version of Record published: June 12, 2019 (version 2)
Copyright
© 2019, Kast et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,273
- views
-
- 369
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Developmental Biology
Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries and play a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular disease and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating dedifferentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that arterial specification of CoW endothelial cells (ECs) occurs after their migration from cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors after they were recruited to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity and wall shear stress. Furthermore, pulsatile flow induces differentiation of human brain PDGFRB+ mural cells into VSMCs, and blood flow is required for VSMC differentiation on zebrafish CoW arteries. Consistently, flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight blood flow activation of endothelial klf2a as a mechanism regulating initial VSMC differentiation on vertebrate brain arteries.
-
- Developmental Biology
Precise developmental timing control is essential for organism formation and function, but its mechanisms are unclear. In C. elegans, the microRNA lin-4 critically regulates developmental timing by post-transcriptionally downregulating the larval-stage-fate controller LIN-14. However, the mechanisms triggering the activation of lin-4 expression toward the end of the first larval stage remain unknown. We demonstrate that the transmembrane transcription factor MYRF-1 is necessary for lin-4 activation. MYRF-1 is initially localized on the cell membrane, and its increased cleavage and nuclear accumulation coincide with lin-4 expression timing. MYRF-1 regulates lin-4 expression cell-autonomously and hyperactive MYRF-1 can prematurely drive lin-4 expression in embryos and young first-stage larvae. The tandem lin-4 promoter DNA recruits MYRF-1GFP to form visible loci in the nucleus, suggesting that MYRF-1 directly binds to the lin-4 promoter. Our findings identify a crucial link in understanding developmental timing regulation and establish MYRF-1 as a key regulator of lin-4 expression.