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Cited by 48

The DOI matches its Crossref record; 90 of the 90 references it cites were found in a registry or an index.

Cortical Foxp2 Supports Behavioral Flexibility and Developmental Dopamine D1 Receptor Expression

Co, Marissa, Hickey, Stephanie L, Kulkarni, Ashwinikumar, Harper, Matthew, Konopka, Genevieve·2020·Cerebral Cortex
DOI 10.1093/cercor/bhz209

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Abstract

Genetic studies have associated FOXP2 variation with speech and language disorders and other neurodevelopmental disorders (NDDs) involving pathology of the cortex. In this brain region, FoxP2 is expressed from development into adulthood, but little is known about its downstream molecular and behavioral functions. Here, we characterized cortex-specific Foxp2 conditional knockout mice and found a major deficit in reversal learning, a form of behavioral flexibility. In contrast, they showed normal activity levels, anxiety, and vocalizations, save for a slight decrease in neonatal call loudness. These behavioral phenotypes were accompanied by decreased cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified at least five excitatory and three inhibitory D1R-expressing cell types in neonatal frontal cortex, and we found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Strikingly, these alterations included non-cell-autonomous changes in upper layer neurons and interneurons. Together, these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits and behaviors relevant to NDDs.

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Crossref · 10.1093/cercor/bhz209

Cites

90 of 90 references verified0 citation errors · 0 not checkable

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Figures

Figure 1 Foxp2 cKO mice show behavioral inflexibility but normal vocalizations. (A) Breeding scheme to generate control ( Foxp2 flox/flox ) and Foxp2 cKO ( Emx1-Cre; Foxp2 flox/flox ) littermate mice. (B-C) Reversal learning in water Y-maze. n = 10-17 per condition. (B) Fraction of correct trials. Data are shown as means (±SEM). (*) P < 0.05, (**) P < 0.01, two-way ANOVA with Bonferroni's multiple comparisons test. (C) Number of trials to criterion. Box shows 25-75 percentiles, whiskers show min-max. (*) P < 0.05, t-test. (D-G) Analysis of USVs. (D) Adult courtship USVs. Box shows 25-75 percentiles,
Figure 1 Foxp2 cKO mice show behavioral inflexibility but normal vocalizations. (A) Breeding scheme to generate control ( Foxp2 flox/flox ) and Foxp2 cKO ( Emx1-Cre; Foxp2 flox/flox ) littermate mice. (B-C) Reversal learning in water Y-maze. n = 10-17 per condition. (B) Fraction of correct trials. Data are shown as means (±SEM). (*) P < 0.05, (**) P < 0.01, two-way ANOVA with Bonferroni's multiple comparisons test. (C) Number of trials to criterion. Box shows 25-75 percentiles, whiskers show min-max. (*) P < 0.05, t-test. (D-G) Analysis of USVs. (D) Adult courtship USVs. Box shows 25-75 percentiles,CC-BY-NC-ND · From the PDF
Image 2
CC-BY-NC-ND · From the PDF
Figure 3 Foxp2 cKO mice show altered composition of dopamine D1 receptorexpressing neuronal subtypes. (A) Experimental design for D1R scRNA-seq. n = 2 per condition. (B) UMAP projection of clusters with neurons combined from both genotypes. (C) Hypergeometric overlaps of neuronal cluster marker genes with P0 mouse cortex cluster marker genes from Loo et al 2019. (D) Violin plots of selected marker genes. Yaxes show log-scaled expression. (E) Percentage of control and cKO cells per cluster. (**) P < 0.01, (****) P < 0.0001, Fisher's exact test with Benjamini-Hochberg post-hoc test. (F) IHC for tdTomato and SP9 in P7 control and cKO mPFC. Pial surface is at the top. Arrowheads indicate cells expressing both proteins. Scale bar: 200 µm. (G) Percentage of cells expressing SP9 ± tdTomato in P7 control and cKO mPFC. Data are represented
Figure 3 Foxp2 cKO mice show altered composition of dopamine D1 receptorexpressing neuronal subtypes. (A) Experimental design for D1R scRNA-seq. n = 2 per condition. (B) UMAP projection of clusters with neurons combined from both genotypes. (C) Hypergeometric overlaps of neuronal cluster marker genes with P0 mouse cortex cluster marker genes from Loo et al 2019. (D) Violin plots of selected marker genes. Yaxes show log-scaled expression. (E) Percentage of control and cKO cells per cluster. (**) P < 0.01, (****) P < 0.0001, Fisher's exact test with Benjamini-Hochberg post-hoc test. (F) IHC for tdTomato and SP9 in P7 control and cKO mPFC. Pial surface is at the top. Arrowheads indicate cells expressing both proteins. Scale bar: 200 µm. (G) Percentage of cells expressing SP9 ± tdTomato in P7 control and cKO mPFC. Data are representedCC-BY-NC-ND · From the PDF
Figure 4 Cortical Foxp2 deletion induces non-cell-autonomous dysregulation of cytoskeletal genes. (A) Identification of differentially expressed genes (DEGs) between all control and all Foxp2 cKO neurons from D1R scRNA-seq. (B) Number of DEGs significantly down- or upregulated in cKO neurons. (C) Number (left) and hypergeometric enrichment (right) of DEGs among neuronal cluster marker genes. Gray shaded area indicates clusters with Foxp2 enrichment. (D) Summarized gene ontology (GO) Biological Process terms for down- and upregulated DEGs. (E) Analysis of DEGs by cluster between control and cKO neurons. (F) Number of DEGs per cluster with selected genes shown.
Figure 4 Cortical Foxp2 deletion induces non-cell-autonomous dysregulation of cytoskeletal genes. (A) Identification of differentially expressed genes (DEGs) between all control and all Foxp2 cKO neurons from D1R scRNA-seq. (B) Number of DEGs significantly down- or upregulated in cKO neurons. (C) Number (left) and hypergeometric enrichment (right) of DEGs among neuronal cluster marker genes. Gray shaded area indicates clusters with Foxp2 enrichment. (D) Summarized gene ontology (GO) Biological Process terms for down- and upregulated DEGs. (E) Analysis of DEGs by cluster between control and cKO neurons. (F) Number of DEGs per cluster with selected genes shown.CC-BY-NC-ND · From the PDF
Figure 5 Identification of genes directly regulated by Foxp2 in the cortex. (A) Top: Analysis of genes correlated or anticorrelated with Foxp2 expression across control neurons from D1R scRNA-seq. Bottom: Number of Foxp2 -correlated or -anticorrelated genes. (B) Overlap of Foxp2 -correlated or -anticorrelated genes with embryonic brain Foxp2 ChIP-chip targets from (Vernes et al. 2011) and with neuronal cluster marker genes. CR: Cajal-Retzius, CTh: corticothalamic, INT: interneuron, IT: intratelencephalic, Mig INT: migrating interneuron, NP: near-projecting.
Figure 5 Identification of genes directly regulated by Foxp2 in the cortex. (A) Top: Analysis of genes correlated or anticorrelated with Foxp2 expression across control neurons from D1R scRNA-seq. Bottom: Number of Foxp2 -correlated or -anticorrelated genes. (B) Overlap of Foxp2 -correlated or -anticorrelated genes with embryonic brain Foxp2 ChIP-chip targets from (Vernes et al. 2011) and with neuronal cluster marker genes. CR: Cajal-Retzius, CTh: corticothalamic, INT: interneuron, IT: intratelencephalic, Mig INT: migrating interneuron, NP: near-projecting.CC-BY-NC-ND · From the PDF
Figure 6 Summary of behavioral and molecular findings in Foxp2 cKO mice. CLA: claustrum, CThPNs: corticothalamic projection neurons, D1R: dopamine D1 receptor, ITPNs: intratelencephalic projection neurons, L: layer, mPFC: medial prefrontal cortex, STR: striatum, THAL: thalamus.
Figure 6 Summary of behavioral and molecular findings in Foxp2 cKO mice. CLA: claustrum, CThPNs: corticothalamic projection neurons, D1R: dopamine D1 receptor, ITPNs: intratelencephalic projection neurons, L: layer, mPFC: medial prefrontal cortex, STR: striatum, THAL: thalamus.CC-BY-NC-ND · From the PDF

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  1. Andrews, 2010, Fastqc: a quality control tool for high throughput sequence data
  2. Morgan, 2017, Genereviews((r))Foxp2-related speech and language disorders

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Metadata

Authors
Co, M., Hickey, S. L., Kulkarni, A., Harper, M., & Konopka, G.
Affiliations
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA
ORCID
Konopka, Genevieve
Venue
Cerebral Cortex
Publisher
Oxford University Press (OUP)
Published
2019-11-11
Volume
30
Issue
3
Pages
1855-1870
ISSN
  • 1047-3211
  • 1460-2199
DOI
10.1093/cercor/bhz209
Cited by
48
References
90
Language
en
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Funders
  • National Institutes of Health (T32GM109776, TL1TR001104, DC014702, DC016340, MH102603)
  • Autism Science Foundation (REG 15-002)
  • Simons Foundation (SFARI 573689, 401220)
  • James S. McDonnell Foundation (220020467)
  • Silicon Valley Community Foundation (HCA-A-1704-01747)

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