Control of Huntington’s Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2

Hachigian, Lea J.; Carmona, Vítor; Fenster, Robert J.; Kulicke, Ruth; Heilbut, Adrian; Sittler, Annie; Almeida, Luís Pereira de; Mesirov, Jill P.; Gao, Fan; Kolaczyk, Eric D.; Heiman, Myriam

doi:10.1016/j.celrep.2017.11.018

Cited by 24 publications

(13 citation statements)

References 40 publications

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“…This variability was not seen in cortical or cerebellar Foxp2 cKO mice, indicating a specific role for striatal Foxp2 in controlling motor variability. Another study performed viral Foxp2 knockdown in the adult striatum to assess its roles in Huntington's disease-related phenotypes, which include motor impairments (Hachigian et al, 2017). This knockdown decreased the latency for mice to fall off the rotarod, and also reduced vertical activity, rearing, and climbing in an open field.…”

Section: Striatum-specific Foxp2 Manipulationsmentioning

confidence: 99%

FOXP transcription factors in vertebrate brain development, function, and disorders

Anderson

Konopka

2020

WIREs Developmental Biology

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FOXP transcription factors are an evolutionarily ancient protein subfamily coordinating the development of several organ systems in the vertebrate body. Association of their genes with neurodevelopmental disorders has sparked particular interest in their expression patterns and functions in the brain. Here, FOXP1, FOXP2, and FOXP4 are expressed in distinct cell type‐specific spatiotemporal patterns in multiple regions, including the cortex, hippocampus, amygdala, basal ganglia, thalamus, and cerebellum. These varied sites and timepoints of expression have complicated efforts to link FOXP1 and FOXP2 mutations to their respective developmental disorders, the former affecting global neural functions and the latter specifically affecting speech and language. However, the use of animal models, particularly those with brain region‐ and cell type‐specific manipulations, has greatly advanced our understanding of how FOXP expression patterns could underlie disorder‐related phenotypes. While many questions remain regarding FOXP expression and function in the brain, studies to date have illuminated the roles of these transcription factors in vertebrate brain development and have greatly informed our understanding of human development and disorders. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Nervous System Development > Vertebrates: Regional Development

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Section: Striatum-specific Foxp2 Manipulationsmentioning

confidence: 99%

FOXP transcription factors in vertebrate brain development, function, and disorders

Anderson

Konopka

2020

WIREs Developmental Biology

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“…While Drd3-MSN and Grm8-MSN clusters were relatively depleted in the classic MSN marker Ppp1r1b (the gene encoding DARPP-32 protein) (25), each cluster exhibited high expression of Foxp2 and Bcl11b, genes strongly linked to MSN differentiation and function ( Supplementary Fig. 2) (26)(27)(28). Moreover, whereas cell fractions in nearly all clusters were evenly distributed between treatment group (saline and cocaine) and sex, 91% of Drd3-MSNs were found in male animals, indicative of a significant sex bias in this subpopulation (Supplementary Fig.…”

Section: Genesmentioning

confidence: 99%

A dopamine-induced gene expression signature regulates neuronal function and cocaine response

Savell

Zipperly

Tuscher

et al. 2019

Preprint

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Drug addiction is a worldwide health problem, with overdose rates of both psychostimulants and opioids currently on the rise in many developed countries. Drugs of abuse elevate dopamine levels in the nucleus accumbens (NAc) and alter transcriptional programs believed to promote long-lasting synaptic and behavioral adaptations. However, even with well-studied drugs such as cocaine, druginduced transcriptional responses remain poorly understood due to the cellular heterogeneity of the NAc and complex drug actions via multiple neurotransmitter systems. Here, we leveraged highthroughput single-nucleus RNA-sequencing to create a comprehensive molecular atlas of cell subtypes in the NAc, defining both sex-specific and cell type-specific responses to acute cocaine experience in a rat model system. Using this transcriptional map, we identified specific neuronal subpopulations that are activated by cocaine, and defined an immediate early gene expression program that is upregulated following cocaine experience in vivo and dopamine (DA) receptor activation in vitro. To characterize the neuronal response to this DA-mediated gene expression signature, we engineered a large-scale CRISPR/dCas9 activation strategy to recreate this program. Multiplexed induction of this gene program initiated a secondary synapse-centric transcriptional profile, altered striatal physiology in vitro, and enhanced cocaine sensitization in vivo. Taken together, these results define the genome-wide transcriptional response to cocaine with cellular precision, and demonstrate that drug-responsive gene programs are sufficient to initiate both physiological and behavioral adaptations to drugs of abuse.NEARLY 5 MILLION Americans reported cocaine use in 2017, and recent increases in cocaine-related drug overdoses present significant public health challenges (1). A hallmark trait of drugs of abuse is the acute elevation of dopamine (DA) in the nucleus accumbens (NAc), a central integrator of the reward circuit (2-4). Abused drugs produce increases in DA that are greater in both concentration and duration than natural rewards (2,5,6), and this signaling is hypothesized to underlie maladaptive reinforcement after repeated drug use (7). Exposure to drugs of abuse results in significant transcriptional and epigenetic reorganization in the NAc (8-13), initiating synaptic and behavioral plasticity associated with the transition to drug addiction (7,14,15). However, even with well-studied drugs such as cocaine, drug-induced transcriptional responses remain poorly understood. This is in part due to the cellular heterogeneity of the NAc, which is a diverse structure containing multiple neuronal and non-neuronal subpopulations and complex neuronal circuitry. Additionally, many drugs of abuse engage multiple neurotransmitter systems in the NAc (16-22), and the specific contributions of DA-dependent transcriptional programs to neuronal physiology and behavior is not clear. Further, although drug experience leads to large scale transcriptional changes in the NAc, previou...

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“…Two well-characterized transcription factors (TFs) with enriched expression in the striatum, Bcl11b/Ctip2 and Foxp2, are decreased in some HD models, although Foxp2 is not decreased in patients. Both appear to interact with mHtt, as determined by co-immunoprecipitation [81,82]. Bcl11b overexpression in STHdhQ111 cells rescues mitochondrial metabolic activity [81], but only Foxp2 contribution to HD pathology has been evaluated in vivo.…”

Section: Intrinsic Vulnerability Of Msnsmentioning

confidence: 99%

“…Bcl11b overexpression in STHdhQ111 cells rescues mitochondrial metabolic activity [81], but only Foxp2 contribution to HD pathology has been evaluated in vivo. Interestingly, Foxp2 overexpression in the BACHD model rescues motor coordination deficits, whereas knockdown in wild-type mice leads to symptoms overlapping with those of HD, both unsurprisingly implying cell-autonomous effects [82]. Much work, however, remains to determine whether any individual striatal-enriched gene, or their combination, actually accounts for MSN vulnerability.…”

Section: Intrinsic Vulnerability Of Msnsmentioning

confidence: 99%

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Creus-Muncunill

Ehrlich

2019

Neurotherapeutics

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Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion in the trinucleotide CAG repeat in exon-1 in the huntingtin gene, located on chromosome 4. When the number of trinucleotide CAG exceeds 40 repeats, disease invariably is manifested, characterized by motor, cognitive, and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form (mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain regions are affected, the most vulnerable brain region is the striatum. Striatal medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the cortical pyramidal neurons located in layers V and VI. Proposed HD pathogenic mechanisms include, but are not restricted to, excitotoxicity, neurotrophic support deficits, collapse of the protein degradation mechanisms, mitochondrial dysfunction, transcriptional alterations, and disorders of myelin. Studies performed in cell type-specific and regionally selective HD mouse models implicate both MSN cell-autonomous properties and cell-cell interactions, particularly corticostriatal but also with non-neuronal cell types. Here, we review the intrinsic properties of MSNs that contribute to their selective vulnerability and in addition, we discuss how astrocytes, microglia, and oligodendrocytes, together with aberrant corticostriatal connectivity, contribute to HD pathophysiology. In addition, mHtt causes cell-autonomous dysfunction in cell types other than MSNs. These findings have implications in terms of therapeutic strategies aimed at preventing neuronal dysfunction and degeneration.

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Control of Huntington’s Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2

Cited by 24 publications

References 40 publications

FOXP transcription factors in vertebrate brain development, function, and disorders

FOXP transcription factors in vertebrate brain development, function, and disorders

A dopamine-induced gene expression signature regulates neuronal function and cocaine response

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

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