Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

Abstract

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.

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

“…1 E-b and 1E-c , respectively). CTIP2 identifies migrating neurons and deep cortical layers V/VI, whereas FOXP2 expression in the developing cortex is restricted to subpopulations of post-mitotic neurons in deep cortical layers (V/VI) 73 , 93 . These elaborate cellular laminar organization and architectures are very similar to what was observed in human brains 94 – 96 .…”

“…Fixed cerebral organoid tissue sections with 4-µm thickness were stained with the following primary antibodies: paired box protein 6 (PAX6, a neural stem cell marker 64 , 65 ), microtubule-associated protein 2 (MAP2: a neuron-specific marker), synapsin1 (a synapse marker), S100 calcium-binding protein β (S100β: an astrocyte marker), doublecortin (an immature and migrating neuron marker 66 , 67 ), SRY-Box Transcription Factor 2 (SOX2: a neural stem cell marker 68 ), Forkhead box G1 (FOXG1: a forebrain marker 56 , 65 , 69 , 70 ), prealbumin (also called TTR: a choroid plexus marker 65 , 71 ), COUP-TF-interacting protein 2 (CTIP2: a V/VI cortical layer migrating neuron marker 65 , 69 , 70 ), and FOXP2 (a VI cortical layer neuron marker 72 , 73 ), and cleaved (or activated) caspase 3 (an apoptosis marker). Slides were imaged by Olympus slide scanners (Olympus, Shinjuku City, Tokyo, Japan).…”

Behavior-related gene regulatory networks: A new level of organization in the brain

“…Knockdown of FoxP2 is known to impact vocal imitation and song variability. Mechanistic studies have shown FoxP2 to regulate genes that contribute to neurite outgrowth and NN formation (51), and to influence dopamine-modulated cortical circuits (54) in the mouse brain. Similarly, in the Drosophila brain, complex regulatory cascades of gene expression establish specific features of Tv1 neurons such as neurite morphology or neurotransmitter identity (55).…”

Interactome, Network, and Enrichment Motif Analysis Reveals Possible Linkage Between Human Mental Disorders, Emotions, and Coronavirus: In-Silico Insight

“…FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. cortex-speci c Foxp2 conditional knockout mice and found a major de cit in reversal learning, a form of behavioral exibility (39,40). and inhuman (41).…”