FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

Araujo, Daniel J.; Anderson, Ashley G.; Berto, Stefano; Runnels, Wesley; Harper, Matthew; Ammanuel, Simon; Rieger, Michael A.; Huang, Hung Chung; Rajkovich, Kacey; Loerwald, Kristofer W.; Dekker, Joseph D.; Tucker, Haley O.; Dougherty, Joseph D.; Gibson, Jay R.; Konopka, Genevieve

doi:10.1101/gad.267989.115

Cited by 93 publications

(139 citation statements)

References 83 publications

(102 reference statements)

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“…This targeting information, combined with the neural expression of miR-873-5p and its host gene LINGO2, strongly suggest a potential regulatory role in synapse development and function. We also found that the miR-873-5p variant binds to the transcription factor FOXP1 transcript, suggesting a dysregulation of FOXP1 expression, which has previously been shown to play a critical regulatory role in CNTNAP2 expression [83], as well as a functional role of striatal pathways important for vocal communication [84]. Despite this miRNA mutation being inherited from an unaffected parent, the measurable loss-of-binding in several ASD-risk genes leads us to postulate that it may contribute additively to ASD risk, particularly when combined with the mutation load from the mother with recorded BAP.…”

Section: Discussionmentioning

confidence: 51%

An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder

Williams

Edson

et al. 2018

Mol Psychiatry

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A number of genetic studies have identified rare protein-coding DNA variations associated with autism spectrum disorder (ASD), a neurodevelopmental disorder with significant genetic etiology and heterogeneity. In contrast, the contributions of functional, regulatory genetic variations that occur in the extensive non-protein-coding regions of the genome remain poorly understood. Here we developed a genome-wide analysis to identify the rare single nucleotide variants (SNVs) that occur in non-coding regions and determined the regulatory function and evolutionary conservation of these variants. Using publicly available datasets and computational predictions, we identified SNVs within putative regulatory regions in promoters, transcription factor binding sites, and microRNA genes and their target sites. Overall, we found that the regulatory variants in ASD cases were enriched in ASD-risk genes and genes involved in fetal neurodevelopment. As with previously reported coding mutations, we found an enrichment of the regulatory variants associated with dysregulation of neurodevelopmental and synaptic signaling pathways. Among these were several rare inherited SNVs found in the mature sequence of microRNAs predicted to affect the regulation of ASD-risk genes. We show a paternally inherited miR-873-5p variant with altered binding affinity for several risk-genes including NRXN2 and CNTNAP2 putatively overlay maternally inherited lossof-function coding variations in NRXN1 and CNTNAP2 to likely increase the genetic liability in an idiopathic ASD case. Our analysis pipeline provides a new resource for identifying loss-of-function regulatory DNA variations that may contribute to the genetic etiology of complex disorders.

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Section: Discussionmentioning

confidence: 51%

An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder

Williams

Edson

et al. 2018

Mol Psychiatry

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“…Measuring USVs is widely carried out in genetic ASD model mice (63), with phenotypes observed in models of Foxp1 (64), Cntnap2 (52), Tsc1 (20), Tsc2 (65), Nlgn3 (66), Nlgn4 (67), Shank1 (68), Shank2 (69), Shank3 (70) and Mecp2 (71). In support of our behavioral results, two recent studies have demonstrated that sumoylation in hippocampus can modify mammalian cognitive behaviors by altering hippocampal-dependent learning and memory by Ubc9, a E2 conjugating enzyme (72), and spatial memory by sumoylation of CREB (73).…”

Section: Discussionmentioning

confidence: 99%

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

Usui

Harper

et al. 2017

Biological Psychiatry

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Background Mutations in the gene encoding the transcription factor forkhead box P2, FOXP2, result in brain developmental abnormalities including reduced gray matter in both human patients and rodent models, and speech and language deficits. However, neither the region-specific function of FOXP2 in the brain, in particular the cerebellum, nor the effects of any post-translational modifications of FOXP2 in the brain and disorders have been explored. Methods We characterized sumoylation of FOXP2 biochemically, and analyzed the region-specific function and sumoylation of FOXP2 in the developing mouse cerebellum. Using in utero electroporation to manipulate the sumoylation-state of Foxp2 as well as Foxp2 expression levels in Purkinje cells (PCs) of the cerebellum in vivo, we reduced Foxp2 expression approximately 40% in the mouse cerebellum. Such a reduction approximates the haploinsufficiency observed in human patients who demonstrate speech and language impairments. Results We identified sumoylation of FOXP2 at K674 (K673 in mouse) in the cerebellum of neonates. In vitro co-immunoprecipitation and in vivo colocalization experiments suggest that PIAS3 acts as the SUMO E3 ligase for FOXP2 sumoylation. This sumoylation modifies transcriptional regulation by FOXP2. We demonstrate that Foxp2 sumoylation is required for regulation of cerebellar motor function and vocal communication, likely through dendritic outgrowth and arborization of PCs in the mouse cerebellum. Conclusions Sumoylation of Foxp2 in neonatal mouse cerebellum regulates PC development as well as motor functions and vocal communication, demonstrating evidence for sumoylation in regulating mammalian behaviors.

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“…De novo loss‐of‐function variants in the fork head box P1 ( FOXP1 ) gene have been identified in independent studies of individuals with ASD . Mice with constitutive heterozygous deletion of Foxp1 had reduced ultrasonic vocalizations . Brain‐specific homozygous Foxp1 knockout mice had morphological defects of the developing brain, several behavioral abnormalities, altered neuronal dendritic morphology, and reduced excitability of CA1 hippocampal pyramidal neurons.…”

Section: Transcription Factorsmentioning

confidence: 99%

Autism genetics – an overview

Yin

Schaaf

2016

Prenatal Diagnosis

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Autism spectrum disorder (ASD) is a highly heritable, clinically diverse group of neurodevelopmental disorders. Its genetic heterogeneity is remarkable, with more than 800 ASD predisposition genes identified to date. They are involved in various biological processes, including chromatin remodeling and gene transcription regulation, cell growth and proliferation, ubiquitination, and neuronal-specific processes, such as synaptic organization and activity, dendritic morphology, and axonogenesis. This review aims to discuss basic autism genetics, explicate ways to investigate ASD in model systems, highlight some key genes and their molecular pathways, and introduce novel theories of ASD pathogenesis, such as imbalance of excitatory and inhibitory brain activity, oligogenic heterozygosity, and the female protective model. © 2016 John Wiley & Sons, Ltd.

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FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

Cited by 93 publications

References 83 publications

An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder

An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

Autism genetics – an overview

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