FOXP1 orchestration of ASD-relevant signaling pathways.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE62718 | GEO | 2015/10/26
SECONDARY ACCESSION(S): PRJNA264860
REPOSITORIES: GEO
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Project description:Mutations in the gene encoding the transcription factor forkhead box P1 or FOXP1 occur in patients with neurodevelopmental disorders, including autism. However, the function of FOXP1 in the brain remains mostly unknown. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and mouse brain and demonstrate a conserved role for FOXP1 transcriptional regulation of autism and Fragile X Mental Retardation Protein (FMRP) mediated pathways. Coexpression networks support a role for Foxp1 in neuronal activity, and we show that Foxp1 is necessary for neuronal excitability. Using a Foxp1 mouse model, we observe defects in ultrasonic vocalizations. This behavioral phenotype is reflected at the genomic level as striatal Foxp1-regulated overlap with genes known to be important in rodent vocalizations. These data support an integral role for FOXP1 in regulating signaling pathways vulnerable in developmental disorders and the specific regulation of pathways important for vocal communication. We carried out RNA-sequencing (RNA-seq) and ChIP-sequencing of human neural progenitors cells. We carried out RNA-sequencing (RNA-seq) of mouse striatal tissue, mouse hippocampal tissue and mouse cortical tissue. For the RNA-seq, four indipendent replicates were used for the neural progenitor cells and mouse tissues. For the Chip-seq, a single neural progenitor cell line was used.
2015-10-26 | E-GEOD-62718 | biostudies-arrayexpress
Project description:FOXP1 orchestration of ASD-relevant signaling pathways.
| PRJNA264860 | ENA
Project description:CHD8, encoding a chromatin remodeling protein, is one of the most frequently mutated genes in autism spectrum disorders. However, how such mutations cause autistic behaviors remain unclear. In mice carrying a heterozygous frame-shift mutation in the Chd8 gene (Asn2373LysfsX2) identified in autistic human individuals, we observed autistic-like behaviors that are much stronger in males than in females, similar to human cases. These behaviors included enhanced mother-seeking ultrasonic vocalizations in pups, mother-attachment behaviors in juveniles, and isolation-induced self-grooming in adults. These behaviors were associated with opposite changes in synaptic excitation/inhibition and neuronal firing in male and female mice, but with strong changes in gene expression in female mice. Therefore, this CHD8 mutation may cause male-preponderant autistic-like behaviors in mice through differential synaptic/neuronal changes and gene expression
2018-06-15 | GSE103377 | GEO
Project description:CHD8, encoding a chromatin remodeling protein, is one of the most frequently mutated genes in autism spectrum disorders. However, how such mutations cause autistic behaviors remain unclear. In mice carrying a heterozygous frame-shift mutation in the Chd8 gene (Asn2373LysfsX2) identified in autistic human individuals, we observed autistic-like behaviors that are much stronger in males than in females, similar to human cases. These behaviors included enhanced mother-seeking ultrasonic vocalizations in pups, mother-attachment behaviors in juveniles, and isolation-induced self-grooming in adults. These behaviors were associated with opposite changes in synaptic excitation/inhibition and neuronal firing in male and female mice, but with strong changes in gene expression in female mice. Therefore, this CHD8 mutation may cause male-preponderant autistic-like behaviors in mice through differential synaptic/neuronal changes and gene expression
2018-06-15 | GSE87367 | GEO
Project description:Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected. Factorial design comparing SNCA knock-out mice with wild type littermates in two different tissues (striatum, cerebellum) at two different timepoints (6 and 21 month)
2010-07-21 | E-GEOD-19534 | biostudies-arrayexpress
Project description:Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), ADHD, learning difficulties and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibited strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, and repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals but they did not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs had region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum revealed a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrated a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicated a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents (IPSCs) in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission were altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
2024-07-30 | PXD052868 | Pride
Project description:Astrotactin 2 (ASTN2) is a transmembrane, neuronal protein that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. We recently reported a family with a paternally inherited intragenic ASTN2 duplication, with a range of neurodevelopmental disorders, including autism spectrum disorder (ASD), learning difficulties and speech and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study ASTN2 role in cerebellar circuit function, we generated global and Purkinje cell-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization (USV) calls, increased hyperactivity and repetitive behaviors, altered social behaviors, and impaired cerebellar-dependent eyeblink conditioning. Increased hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrates a large increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous EPSCs, as well as increased amplitudes of both spontaneous EPSCs and IPSCs in the Astn2 KO animals, suggesting that pre- and post-synaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
2024-03-07 | GSE254224 | GEO
Project description:Autism spectrum disorders (ASD) frequently accompany macrocephaly, which could involve hydrocephalic enlargement of brain ventricles. Katnal2 is a microtubule-related protein strongly implicated in ASD. However, it remains unclear whether Katnal2 knockout (KO) in mice leads to microtubule-related cellular deficits and ASD-related phenotypes. We found here that Katnal2-KO mice display social communication deficits, including excessive courtship ultrasonic vocalizations and decreased mating success. Katnal2-KO brains show age-dependent ventricular enlargements and motile ciliary deficits in ependymal cells lining ventricular walls. Katnal2-KO hippocampal neurons, surrounded by lateral ventricles, show limited blood volumes and flow and age-dependent synaptic functional deficits involving synaptic gene downregulation and ASD-like transcriptomic changes. Early postnatal Katnal2 re-expression prevents the ventricular and behavioral phenotypes in Katnal2-KO adults. These results suggest that Katnal2 critically regulates ependymal ciliary function, ventricular volume, CSF circulation, synaptic function, and social communication and that ependymal ciliopathies could underlie ASD-related macrocephaly, ventriculomegaly, and hydrocephalus
2024-03-19 | GSE219228 | GEO
Project description:Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected.
2010-07-22 | GSE19534 | GEO
Project description:Genetic perturbations of the transcription factor, Forkhead Box P1 (FOXP1), occur in patients with autism spectrum disorder who have an increased risk for comorbidity with intellectual disability. Recent work has begun to reveal an important role for Foxp1 in brain development, but the brain region-specific contribution of Foxp1 to autism and intellectual disability phenotypes has yet to be fully determined. Here, we characterize Foxp1 conditional knockout (Foxp1cKO) mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus. Foxp1cKO mice exhibit behavioral phenotypes that are relevant to autism spectrum disorder, including hyperactivity, increased anxiety, and decreased sociability. In addition, Foxp1cKO mice have gross deficits in learning and memory tasks that are relevant to intellectual disability. Using a genome-wide approach, we identified genes differentially expressed in the hippocampus of Foxp1cKO mice that are associated with synaptic function and physiology that could represent molecular networks related to the observed behavioral deficits. Finally, we observed reduced maintenance of long-term potentiation in the CA1 subfield of these animals. Together, these data suggest that expression of Foxp1 in pyramidal neurons of the forebrain is important for regulating gene expression pathways that contribute to specific behaviors relevant to autism and intellectual disability. In particular, Foxp1 regulation of gene expression in the hippocampus appears to be crucial for normal CA1 physiology and spatial learning.
2018-02-13 | GSE97181 | GEO