Generation of mice with a conditional Foxp2 null allele

The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
genesis (Impact Factor: 2.02). 07/2007; 45(7):440-6. DOI: 10.1002/dvg.20305
Source: PubMed


Disruptions of the human FOXP2 gene cause problems with articulation of complex speech sounds, accompanied by impairment in many aspects of language ability. The FOXP2/Foxp2 transcription factor is highly similar in humans and mice, and shows a complex conserved expression pattern, with high levels in neuronal subpopulations of the cortex, striatum, thalamus, and cerebellum. In the present study we generated mice in which loxP sites flank exons 12-14 of Foxp2; these exons encode the DNA-binding motif, a key functional domain. We demonstrate that early global Cre-mediated recombination yields a null allele, as shown by loss of the loxP-flanked exons at the RNA level and an absence of Foxp2 protein. Homozygous null mice display severe motor impairment, cerebellar abnormalities and early postnatal lethality, consistent with other Foxp2 mutants. When crossed to transgenic lines expressing Cre protein in a spatially and/or temporally controlled manner, these conditional mice will provide new insights into the contributions of Foxp2 to distinct neural circuits, and allow dissection of roles during development and in the mature brain.

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Available from: Catherine French, Jan 05, 2014
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    • "sler et al . , 2007 ; Schulz et al . , 2010 ) . In mice , heterozygous and homozygous Foxp2 knockouts as well as humanized knockins have been studied , and a mouse model has been developed with a conditional null ( floxed ) allele , allowing crosses to transgenic lines expressing Cre drivers for tissue - and time - specific conditional knockouts ( French et al . , 2007 ) . Knockdown ( in finches ) or haploinsufficiency ( in mice ) of Foxp2 leads to altered or inaccurate vocalizations ( Shu et al . , 2005 ; Haesler et al . , 2007 ) , and in the finch this is associated with the altered density of spiny neurons in Area X ( Schulz et al . , 2010 ) . Interestingly , the human version of Foxp2 has strong e"
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    ABSTRACT: A number of recent studies have revealed correspondences between song-and language-related neural structures, pathways, and gene expression in humans and songbirds. Analyses of vocal learning, song structure, and the distribution of song elements have similarly revealed a remarkable number of shared characteristics with human speech. This article reviews recent developments in the understanding of these issues with reference to the phonological phenomena observed in human language. This investigation suggests that birds possess a host of abilities necessary for human phonological computation, as evidenced by behavioral, neuroanatomical, and molecular genetic studies. Vocal-learning birds therefore present an excellent model for studying some areas of human phonology, though differences in the primitives of song and language as well as the absence of a human-like morphosyntax make human phonology differ from birdsong phonology in crucial ways.
    Frontiers in Psychology 07/2015; 6:1082. DOI:10.3389/fpsyg.2015.01082 · 2.80 Impact Factor
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    • "Reviews describe the array of Foxp2 model findings consistent with abnormal vocal development and performance (for example, disrupted synaptic plasticity in the striatum, cerebellar and radial glial cell abnormalities, abnormal esophageal development and mild to severe motor impairment) (for example, see [31-37]). Homozygous null Foxp2 mice have cerebellar abnormalities with incompletely folded folia, as well as embryonic, neonatal or perinatal lethality, whereas the heterozygous mutation does not result in premature death but is associated with modest developmental delay, abnormal motor learning and a significant alteration in ultrasonic vocalization in response to parental separation (for example, see [38-40]). "
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    ABSTRACT: Childhood apraxia of speech (CAS) is a rare, severe, persistent pediatric motor speech disorder with associated deficits in sensorimotor, cognitive, language, learning and affective processes. Among other neurogenetic origins, CAS is the disorder segregating with a mutation in FOXP2 in a widely studied, multigenerational London family. We report the first whole-exome sequencing (WES) findings from a cohort of 10 unrelated participants, ages 3 to 19 years, with well-characterized CAS. As part of a larger study of children and youth with motor speech sound disorders, 32 participants were classified as positive for CAS on the basis of a behavioral classification marker using auditory-perceptual and acoustic methods that quantify the competence, precision and stability of a speaker's speech, prosody and voice. WES of 10 randomly selected participants was completed using the Illumina Genome Analyzer IIx Sequencing System. Image analysis, base calling, demultiplexing, read mapping, and variant calling were performed using Illumina software. Software developed in-house was used for variant annotation, prioritization and interpretation to identify those variants likely to be deleterious to neurodevelopmental substrates of speech-language development. Among potentially deleterious variants, clinically reportable findings of interest occurred on a total of five chromosomes (Chr3, Chr6, Chr7, Chr9 and Chr17), which included six genes either strongly associated with CAS (FOXP1 and CNTNAP2) or associated with disorders with phenotypes overlapping CAS (ATP13A4, CNTNAP1, KIAA0319 and SETX). A total of 8 (80%) of the 10 participants had clinically reportable variants in one or two of the six genes, with variants in ATP13A4, KIAA0319 and CNTNAP2 being the most prevalent. Similar to the results reported in emerging WES studies of other complex neurodevelopmental disorders, our findings from this first WES study of CAS are interpreted as support for heterogeneous genetic origins of this pediatric motor speech disorder with multiple genes, pathways and complex interactions. We also submit that our findings illustrate the potential use of WES for both gene identification and case-by-case clinical diagnostics in pediatric motor speech disorders.
    Journal of Neurodevelopmental Disorders 10/2013; 5(1):29. DOI:10.1186/1866-1955-5-29 · 3.27 Impact Factor
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    • "Foxp1 and Foxp2 expression overlaps in the striatum, thalamus, superior colliculus and inferior olive in the mature mouse brain, but their expression differs in other regions including the cortex, hippocampus and inferior colliculus (Ferland et al. 2003). It is interesting that histological analyses of brains from Foxp2 knockout mice only revealed gross morphological abnormalities in the cerebellum, where Foxp1 is not co-expressed (French et al. 2007), suggesting that Foxp1 may compensate for the loss of Foxp2 and that a level of redundancy exists between these two genes. It will be interesting to see whether layers 3, 4 and 5 of the cortex or the hippocampus which express Foxp1 only are exclusively abnormal in the Foxp1 knockout mouse. "
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    Human Genetics 06/2012; 131(11):1687-98. DOI:10.1007/s00439-012-1193-z · 4.82 Impact Factor
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