Twist1 Plays an Anti-apoptotic Role in Mutant Huntingtin Expression Striatal Progenitor Cells

  • Wei-Ping Jen
  • Hui-Mei Chen
  • Yow-Sien Lin
  • Yijuang Chern
  • Yi-Ching LeeEmail author


The Twist basic helix-loop-helix transcription factor 1 (Twist1) has been implicated in embryogenesis and carcinogenesis, due to its effects on cell proliferation and anti-apoptosis signaling. Interestingly, a connection between Twist1 and neurotoxicity was recently made in mutant huntingtin (mHtt)-expressing primary cortical neurons; however, the role of Twist1 in Huntington’s disease (HD)-affected striatal neurons remains undescribed. In this study, we evaluated the expression and function of Twist1 in the R6/2 HD mouse model, which expresses the polyQ-expanded N-terminal portion of human HTT protein, and a pair of striatal progenitor cell lines (STHdhQ109 and STHdhQ7), which express polyQ-expanded or non-expanded full-length mouse Htt. We further probed upstream signaling events and Twist1 anti-apoptotic function in the striatal progenitor cell lines. Twist1 was increased in mHtt-expressing striatal progenitor cells (STHdhQ109) and was correlated with disease progression in striatum and cortex brain regions of R6/2 mice. In the cell model, downregulation of Twist1 induced death of STHdhQ109 cells but had no effect on wild-type striatal progenitor cells (STHdhQ7). Twist1 knockdown stimulated caspase-3 activation and apoptosis. Furthermore, we found that signal transducer and activator of transcription 3 (STAT3) were increased in HD striatal progenitor cells and acted as an upstream regulator of Twist1. As such, inhibition of STAT3 induced apoptosis in HD striatal progenitor cells. Our results suggest that mHtt upregulates STAT3 to induce Twist1 expression. Upregulated Twist1 inhibits apoptosis, which may protect striatal cells from death during disease progression. Thus, we propose that Twist1 might play a protective role against striatal degeneration in HD.


Twist1 Huntington’s disease Apoptosis Neuroprotection STAT3 



Analysis of variance


Brown adipose tissue


Bcl-2-associated death promoter


B cell lymphoma 2


Brain-derived neurotrophic factor


Bovine serum albumin


Hippocampal Cornu Ammonis area 1




Cannabinoid receptor type 1 receptor


Cleaved caspase-3


Complementary DNA


Cyan fluorescent protein


Central nervous system


Dulbecco’s modified Eagle medium




Epithelial-mesenchymal transition


Histone 3 lysine 4 trimethylation


Huntington’s disease


Hypoxia-inducible factors


Humanized recombinant green fluorescent protein




Insulin resistant


Mutant huntingtin


3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide


Nuclear factor kappa-light-chain-enhancer of activated B cells


Phosphate-buffered saline


Polymerase chain reaction


PPAR gamma coactivator 1-alpha


Propidium iodide


Peripheral nervous system




Peroxisome proliferator-activated receptor


Phosphorylated form of STAT3


Real-time quantitative qPCR


Signal transducer and activator of transcription 3


Sodium dodecyl sulfate


Sodium dodecyl sulfate polyacrylamide gel electrophoresis


Mutant huntingtin striatal progenitor cells


Wild-type striatal progenitor cells


Twist basic helix-loop-helix transcription factor 1


Transcription factor


Tumor necrosis factor alpha


Tropomyosin receptor kinase B


Valosin-containing protein


Western blot





We are grateful to Dr. Elena Cattaneo (University of Milano, Italy) for providing the striatal cell lines (STHdhQ7, and STHdhQ109). We thank Dr. Kou-Juey Wu (Chang Gung Memorial Hospital, Taiwan) for providing the sh1-Ctrl and sh1-Twist1 constructs. We thank Ms. Shu-Chen Shen (Advanced Optical Microscope Core Facility, Scientific Instrument Center of Academia Sinica) for the technical assistance of confocal microscopy. We also thank Ms. Chia-Chen Dai and Tzu-Wen Tai (Flow Cytometry Core Facility of the Institute of Biomedical Sciences, Academia Sinica) for the technical support with cell sorting. We are also grateful to the RNAi Core Facility (Academia Sinica) and DNA Sequencing Core Facility (IBMS, Academia Sinica) for their help. We also thank Dr. Marcus J. Calkins for reading and editing the manuscript.

Authors’ Contributions

WPJ conceived research, designed experiments, performed and analyzed real-time qPCR, immunofluorescence staining, IHC, western blotting (except brain nuclear-cytosolic fractionation results), cell culture and preparation, cell survival assay, and annexin V/PI apoptosis analysis, Seahorse Mito Stress assay, and wrote the manuscript. HMC maintained the mice used in this study. YSL carried out nuclear-cytosolic fractionation results. YCL and YC refined the experimental design and edited the manuscript. All authors read and approved the final manuscript.

Funding Information

This work was supported by grants from the Ministry of Science and Technology (NSC97-2321-B-001-030, NSC98-2321-B-001-017, NSC99-2321-B-001-012, NSC100-2321-B-001-00, 104-2321-B-001-063) and Academia Sinica (AS-100-TP2-B02), Taiwan.

Compliance with Ethical Standards

Animal experiments were performed in accordance with the protocols approved by the Academia Sinica Institutional Animal Care and Utilization Committee.

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12035_2019_1836_MOESM1_ESM.pdf (14.3 mb)
ESM 1 (PDF 14629 kb)


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Authors and Affiliations

  1. 1.Graduate Institute of Life SciencesNational Defense Medical CenterTaipeiTaiwan
  2. 2.Institute of Cellular and Organismic BiologyAcademia SinicaTaipeiTaiwan
  3. 3.Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan

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