Differential effects of Foxp2 disruption in distinct motor circuits

French, Catherine A.; Vinueza-Veloz, María Fernanda; Zhou, Kai; Peter, Saša; Fisher, Simon E.; Costa, Rui M.; Zeeuw, Chris I. De

doi:10.1038/s41380-018-0199-x

Cited by 36 publications

(61 citation statements)

References 76 publications

(118 reference statements)

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“…We observed no gross abnormalities in brain morphology of cKO mice (Supplemental Fig. 1), consistent with a previous study utilizing the same conditional knockout strategy (French et al 2018).…”

Section: Cortical Foxp2 Deletion Impairs Behavioral Flexibilitysupporting

confidence: 92%

“…2I, Table 1). These results agree with the finding of unaltered neuronal density in L5-6 of adult mice lacking Foxp2 through the same conditional knockout strategy (French et al 2018). Interestingly, although nearly all (~92%) control TLE4+ neurons were Foxp2+/D1R+, ~41% of TLE4+ neurons still maintained D1R expression after Foxp2 deletion ( Fig.…”

Section: Cthpnssupporting

confidence: 90%

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Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

Hickey

Kulkarni

et al. 2019

Preprint

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FoxP2 encodes a forkhead box transcription factor required for the development of neural circuits underlying language, vocalization, and motor-skill learning. Human genetic studies have associated FOXP2 variation with neurodevelopmental disorders (NDDs), and within the cortex, it is coexpressed and interacts with other NDD-associated transcription factors. Cortical Foxp2 is required in mice for proper social interactions, but its role in other NDD-relevant behaviors and molecular pathways is unknown. Here, we characterized such behaviors and their potential underlying cellular and molecular mechanisms in cortex-specific Foxp2 conditional knockout mice. These mice showed deficits in reversal learning without increased anxiety or hyperactivity. In contrast, they emitted normal vocalizations save for a decrease in loudness of neonatal calls. These behavioral phenotypes were accompanied by decreases in cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified neonatal D1R-expressing cell types in frontal cortex and found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Together these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits potentially relevant to NDDs.

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Section: Cortical Foxp2 Deletion Impairs Behavioral Flexibilitysupporting

confidence: 92%

Section: Cthpnssupporting

confidence: 90%

Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

Hickey

Kulkarni

et al. 2019

Preprint

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show abstract

“…In one study, Foxp2 knockdown by IUE of shRNA at E13/14 impaired the transition of radial glia into intermediate progenitors and neurons, and also impaired the migration of neurons into the upper layers of the cortex (Tsui et al, 2013). However, crosses of Foxp2 flox/flox mice with cortical Cre-driver mice have generated cKO mice with normal cortical size, neuronal density, layering, and projections (Co, Hickey, Kulkarni, Harper, & Konopka, 2019;French et al, 2018;Kast et al, 2019;Medvedeva et al, 2018). These discrepancies could result from molecular compensation by other Foxp genes upon genetic Foxp2 deletion, but notably, Foxp1/4 transcripts were not upregulated in cortical neurons in an RNA-seq study of cortical Foxp2 cKO mice (Co et al, 2019).…”

Section: Cortex-specific Foxp2 Manipulationsmentioning

confidence: 99%

FOXP transcription factors in vertebrate brain development, function, and disorders

Anderson

Konopka

2020

WIREs Developmental Biology

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FOXP transcription factors are an evolutionarily ancient protein subfamily coordinating the development of several organ systems in the vertebrate body. Association of their genes with neurodevelopmental disorders has sparked particular interest in their expression patterns and functions in the brain. Here, FOXP1, FOXP2, and FOXP4 are expressed in distinct cell type‐specific spatiotemporal patterns in multiple regions, including the cortex, hippocampus, amygdala, basal ganglia, thalamus, and cerebellum. These varied sites and timepoints of expression have complicated efforts to link FOXP1 and FOXP2 mutations to their respective developmental disorders, the former affecting global neural functions and the latter specifically affecting speech and language. However, the use of animal models, particularly those with brain region‐ and cell type‐specific manipulations, has greatly advanced our understanding of how FOXP expression patterns could underlie disorder‐related phenotypes. While many questions remain regarding FOXP expression and function in the brain, studies to date have illuminated the roles of these transcription factors in vertebrate brain development and have greatly informed our understanding of human development and disorders. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Nervous System Development > Vertebrates: Regional Development

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“…In addition, altered FoxP2 levels in adult Area X affect the dopaminergic modulation of corticostriatal signaling important to song variability and affect song maintenance 12,13 , stressing the fact that tight regulation of FoxP2 expression is a prerequisite for correct neural transmission in differentiated neural circuits. Additional effects of Foxp2 and its disruption on the embryonic development and the function of neural circuits have been described in mice [14][15][16][17][18][19][20][21][22][23] . Further evidence for the biological relevance of tight regulation of FoxP2 expression levels comes from the following studies.…”

Section: Dynamic Foxp2 Levels In Male Zebra Finches Are Linked To Mormentioning

confidence: 99%

Dynamic FoxP2 levels in male zebra finches are linked to morphology of adult-born Area X medium spiny neurons

Kosubek-Langer

Scharff

2020

Sci Rep

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The transcription factor FOXP2 is crucial for the formation and function of cortico-striatal circuits. FOXP2 mutations are associated with specific speech and language impairments. In songbirds, experimentally altered FoxP2 expression levels in the striatal song nucleus Area X impair vocal learning and song production. Overall FoxP2 protein levels in Area X are low in adult zebra finches and decrease further with singing. However, some Area X medium spiny neurons (MSNs) express FoxP2 at high levels (FoxP2 high MSNs) and singing does not change this. Because Area X receives many new neurons throughout adulthood, we hypothesized that the FoxP2 high MSNs are newly recruited neurons, not yet integrated into the local Area X circuitry and thus not active during singing. Contrary to our expectation, FoxP2 protein levels did not predict whether new MSNs were active during singing, assayed via immediate early gene expression. However, new FoxP2 high MSNs had more complex dendrites, higher spine density and more mushroom spines than new FoxP2 low MSNs. In addition, FoxP2 expression levels correlated positively with nucleus size of new MSNs. Together, our data suggest that dynamic FoxP2 levels in new MSNs shape their morphology during maturation and their incorporation into a neural circuit that enables the maintenance and social modulation of adult birdsong.The forkhead box P2 transcription factor (FOXP2) is linked to speech and language disorders. Heterozygous FOXP2 mutations in humans affect both the coordination of fine orofacial movements and language perception 1-3 . Because songbirds -like humans -need to learn most of their communicative vocalizations, they offer a unique model to study the role of FoxP2 (for nomenclature FOXP2/FoxP2 see Methods) for vocal learning and for the maintenance of learned vocalizations as adults 4 . Studying the relationship between FoxP2 and vocal learning in songbirds may inform the neurogenetic mechanism underlying the speech deficits in patients carrying FOXP2 mutations for the following reasons. The FoxP2 protein coding sequence is highly conserved between humans and songbirds as are the brain expression patterns, notably in the cerebellum and striatum 5-7 . Moreover, genetic manipulations of FoxP2 expression levels in the striatal song nucleus Area X during the critical phase of song learning lead to inaccurate and incomplete imitation of the tutor's song and more variable vocal production 3,8-10 . This phenotype bears similarities to the specific speech deficits called developmental verbal dyspraxia, DVD (or childhood apraxia of speech), that patients carrying FOXP2 mutations suffer from. The core-phenotype of DVD consists of altered precision, consistency and sequencing of movements underlying speech in the absence of neuromuscular deficits 11 . In addition, altered FoxP2 levels in adult Area X affect the dopaminergic modulation of corticostriatal signaling important to song variability and affect song maintenance 12,13 , stressing the fact that tight regulation of FoxP2 expressi...

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Differential effects of Foxp2 disruption in distinct motor circuits

Cited by 36 publications

References 76 publications

Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

FOXP transcription factors in vertebrate brain development, function, and disorders

Dynamic FoxP2 levels in male zebra finches are linked to morphology of adult-born Area X medium spiny neurons

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