Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour

Bacon, Claire; Schneider, Miriam; Magueresse, Corentin Le; Froehlich, H.; Sticht, Carsten; Gluch, Christian; Monyer, Hannah; Rappold, Gudrun

doi:10.1038/mp.2014.116

Cited by 119 publications

(121 citation statements)

References 38 publications

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“…Normally, mouse pups subvocalize when separated from their mother; Foxp2 −/− pups do not exhibit this behavior, and Foxp2 +/− pups show a reduction (Shu et al, 2005). No alterations in vocalization were reported for mice with a brain-specific deletion of Foxp1; however, these mice exhibit abnormal cognitive and social behavior, echoing phenotypes in patients with FOXP1 mutations (Bacon et al, 2015).…”

Section: The Foxp Family: Language Acquisition and Cognitive Functionmentioning

confidence: 96%

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Fox transcription factors: from development to disease

2016

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Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development.

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Section: The Foxp Family: Language Acquisition and Cognitive Functionmentioning

confidence: 96%

“…Tissuespecific deletions of FoxP factors also result in developmental defects. For example, mice with a deletion of Foxp1 in neurons are viable but display a morphological change in the striatum and hippocampus (Bacon et al, 2015).…”

Section: The Foxp Family: Language Acquisition and Cognitive Functionmentioning

confidence: 99%

Fox transcription factors: from development to disease

2016

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“…Therefore, understanding how FOXP1 functions within the brain should allow for key insights into the molecular pathways at risk in ASD. Several reports have begun to elucidate a role for Foxp1 in the brain (Rousso et al 2012;Tang et al 2012), and recent work has shown that mice with brain-specific loss of Foxp1 have altered hippocampal electrophysiology, striatal morphology, and social behaviors (Bacon et al 2015). However, the region-specific transcriptional profile of Foxp1 in the mouse brain, how well this profile is conserved in human-relevant Foxp1 haploinsufficient models, and the behavioral consequences of disrupting these regional gene networks remain largely unknown.…”

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confidence: 99%

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

et al. 2015

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Mutations in the transcription factor Forkhead box p1 (FOXP1) are causative for neurodevelopmental disorders such as autism. However, the function of FOXP1 within the brain remains largely uncharacterized. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and patient-relevant heterozygous Foxp1 mouse brains. We demonstrate a role for FoxP1 in the transcriptional regulation of autism-related pathways as well as genes involved in neuronal activity. We show that Foxp1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations. Finally, we demonstrate that FoxP1 has an evolutionarily conserved role in regulating pathways involved in striatal neuron identity through gene expression studies in human neural progenitors with altered FOXP1 levels. These data support an integral role for FoxP1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatal pathways important for vocal communication.

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“…Therefore, these interactions have not been shown in model 4 (Figure 5d) again. FOXP1 (forkhead box protein P1) deletions [98,99] and increase [100] have both been associated with ASD. Both FOXP1 [101] and FOXP2 can downregulate CNTNAP2 (Contactin-associated protein-like 2) [100,102], another candidate gene of ASD [67].…”

Section: Foxp2 and Mir-3666 May Be Responsible For The Pathogenesis Omentioning

confidence: 99%

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

Islam¹

2017

JABB

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MicroRNAs (miRNAs) are approximately 22-nucleotide-long, non-coding RNAs that bind to complementary mRNAs with inhibitory effect. An intronic miRNA is embedded in a particular gene called its host gene. Our study focuses on the Homo sapiens intronic miRNA-host gene pair, hsa-miR-3666 and FOXP2. Previous report of coexpression of miR-3666 and FOXP2 indicates possible regulation of FOXP2 functions by miR-3666. However, direct correlation has not been shown yet. Therefore, we took a computational approach to determine if and how such modulation occurs. ChIP-seq identified FOXP2 targets and putative miR-3666 targets showed a significant overlap of 574 common target genes. Functional enrichment analysis of common targets revealed over-representation of KEGG pathways and Gene Ontology modules associated with neurodevelopment. These modules, along with further literature mining and proteinprotein interaction analysis of FOXP2 and miR-3666 identified several specific genes associated with neurodevelopment and finally integration of transcriptomic expressions data lead to the selection of four models depicting the mechanisms by which miR-3666 can modulate FOXP2 functions. Model 1 illustrates that during neurodevelopment, miR-3666 can directly modulate the functions of FOXP2 through regulation of common targets, such as IGF1 and EFNB2, whereas model 2 shows miR-3666 can also indirectly modulate FOXP2 functions by considering targets that are not common for the intronic miRNA-host gene pair, for example CDH2 and LMO4. This direct and indirect regulation is necessary for precise spatial and temporal expression of genes during neurodevelopment. Models 3 and 4 exhibit mechanisms in which the interactions of miR-3666 and FOXP2 with target genes contribute to the pathogenesis of schizophrenia and autism respectively. a role in transcriptional activation [7]. FOXP2 hosts the intronic miRNA, miR-3666. Though not much work has been done on miR-3666, its targets have been predicted and deposited in various databases. A few recent experiments have shown the repression activity of miR-3666 on targets such as MET and ZEB1 in thyroid carcinoma and cervical carcinoma cells, respectively [9,10].

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Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour

Cited by 119 publications

References 38 publications

Fox transcription factors: from development to disease

Fox transcription factors: from development to disease

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

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