Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Desplats, Paula; Lambert, James R.; Thomas, Elizabeth A.

doi:10.1016/j.nbd.2008.05.005

Cited by 59 publications

(62 citation statements)

References 54 publications

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“…Within the brain, CTIP2 has been described as an integral part of the ATP-dependent chromatin remodeling complex SWI/SNF [59]. CTIP2-induced gene regulation contributes to the specific gene expression profiles of striatal MSNs [60]. Consequently, the increased CTIP2 expression observed in differentiated cells in our study supports the identification of these cells as MSNs.…”

Section: Discussionsupporting

confidence: 81%

In Vitro Differentiation of Human Neural Progenitor Cells Into Striatal GABAergic Neurons

Lin

Yuan

Sander

et al. 2015

Stem Cells Translational Medicine

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Huntington's disease (HD) results from a CAG repeat expansion in the gene encoding the huntingtin protein. This inherited disorder is characterized by progressive neurodegeneration. In particular, HD progression involves the loss of striatal projection neurons. The limited availability of reliable sources of human striatal projection neurons currently hampers our understanding of HD mechanisms and hinders the development of novel HD treatments. In this paper, we described two-and three-step methods for differentiating human neural progenitor cells toward striatal projection neurons. In the two-step differentiation protocol, 90%, 54%, and 6% of MAP2-positive cells were immunopositive for GABA, calbindin (CALB1), and DARPP-32/PPP1R1B, respectively. In the three-step differentiation protocol, 96%, 84%, and 21% of MAP2-positive cells were immunopositive for GABA, calbindin, and DARPP-32/PPP1R1B, respectively. In line with a striatal projection neuron phenotype, cells differentiated with our protocols displayed significantly increased expression of MAP2, CALB1, DARPP-32/PPP1R1B, ARPP21, and CTIP2. Application of glutamate receptor agonists induced calcium influx; accordingly, the cells also expressed various ionotropic glutamate receptor subunits. Differentiated cells also released GABA on stimulation. We suggest that our three-step differentiation protocol presents a reliable and simplified method for the generation of striatal projection neurons, yielding a critical resource for neuronal physiology and neurodegenerative disorder studies. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:775-788 SIGNIFICANCEThe earliest changes in the neurodegenerative disorder Huntington's disease affect a specific type of brain neurons, the so-called medium spiny neurons of the striatum. In this study, two protocols were developed for the differentiation of neural progenitor cells into striatal medium spiny neurons, and the differentiated neurons were extensively characterized. The data indicate that the three-step differentiation protocol presents a reliable and simplified method for the generation of striatal medium spiny neurons. The generated striatal medium spiny neurons could represent a critical resource for the study of neurodegenerative disorders, a model system for drug discovery, and a step toward cellbased regeneration therapies.

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Section: Discussionsupporting

confidence: 81%

In Vitro Differentiation of Human Neural Progenitor Cells Into Striatal GABAergic Neurons

Lin

Yuan

Sander

et al. 2015

Stem Cells Translational Medicine

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“…These include the adenosine 3′,5′-cyclic monophosphate (cAMP) response element-binding protein (CREB)-binding protein, Specificity protein 1, TATA binding box protein, Bcl11b, repressor element-1 transcription factor/neuron restrictive silencer factor, and widely expressed components of the basal polymerase II transcriptional machinery [94,[99][100][101][102][103]. DARPP-32 is the most widely used marker of mature MSNs, and is highly down-regulated in human HD and in the majority of mouse models [44].…”

Section: Transcriptional Dysregulationmentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

126

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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“…qPCR experiments were performed on iCycler iQ5 Real-Time PCR Detection System (Bio-Rad, Hercules, CA) as described. 14 Total RNA was reverse transcribed using iScript cDNA Synthesis kit (Bio-Rad) with 1 mg of total RNA. Amplification was performed on a cDNA amount equivalent to 100 ng total RNA.…”

mentioning

confidence: 99%

Molecular and pathologic insights from latent HIV-1 infection in the human brain

et al. 2013

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Objective: We aimed to investigate whether HIV latency in the CNS might have adverse molecular, pathologic, and clinical consequences.Methods: This was a case-control comparison of HIV-1 seropositive (HIV1) patients with clinical and neuropathologic examination. Based on the levels of HIV-1 DNA, RNA, and p24 in the brain, cases were classified as controls, latent HIV CNS infection, and HIV encephalitis (HIVE). Analysis of epigenetic markers including BCL11B, neurodegeneration, and neuroinflammation was performed utilizing immunoblot, confocal microscopy, immunochemistry/image analysis, and qPCR. Detailed antemortem neurocognitive data were available for 23 out of the 32 cases.Results: HIV1 controls (n 5 12) had no detectable HIV-1 DNA, RNA, or p24 in the CNS; latent HIV1 cases (n 5 10) showed high levels of HIV-1 DNA but no HIV RNA or p24; and HIVE cases (n 5 10) had high levels of HIV-1 DNA, RNA, and p24. Compared to HIV1 controls, the HIV1 latent cases displayed moderate cognitive impairment with neurodegenerative and neuroinflammatory alterations, although to a lesser extent than HIVE cases. Remarkably, HIV1 latent cases showed higher levels of BCL11B and other chromatin modifiers involved in silencing. Increased BCL11B was associated with deregulation of proinflammatory genes like interleukin-6, tumor necrosis factor-a, and CD74. Conclusion:Persistence of latent HIV-1 infection in the CNS was associated with increased levels of chromatin modifiers, including BCL11B. Alteration of these epigenetic factors might result in abnormal transcriptomes, leading to inflammation, neurodegeneration, and neurocognitive impairment. BCL11B and other epigenetic factors involved in silencing might represent potential targets for HIV-1 involvement of the CNS.

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Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Cited by 59 publications

References 54 publications

In Vitro Differentiation of Human Neural Progenitor Cells Into Striatal GABAergic Neurons

In Vitro Differentiation of Human Neural Progenitor Cells Into Striatal GABAergic Neurons

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Molecular and pathologic insights from latent HIV-1 infection in the human brain

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