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Transcriptional repression of the ectodomain sheddase ADAM10 by TBX2 and potential implication for Alzheimer’s disease

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Abstract

Background

The ADAM10-mediated cleavage of transmembrane proteins regulates cellular processes such as proliferation or migration. Substrate cleavage by ADAM10 has also been implicated in pathological situations such as cancer or Morbus Alzheimer. Therefore, identifying endogenous molecules, which modulate the amount and consequently the activity of ADAM10, might contribute to a deeper understanding of the enzyme’s role in both, physiology and pathology.

Method

To elucidate the underlying cellular mechanism of the TBX2-mediated repression of ADAM10 gene expression, we performed overexpression, RNAi-mediated knockdown and pharmacological inhibition studies in the human neuroblastoma cell line SH-SY5Y. Expression analysis was conducted by e.g. real-time RT-PCR or western blot techniques. To identify the binding region of TBX2 within the ADAM10 promoter, we used luciferase reporter assay on deletion constructs and EMSA/WEMSA experiments. In addition, we analyzed a TBX2 loss-of-function Drosophila model regarding the expression of ADAM10 orthologs by qPCR. Furthermore, we quantified the mRNA level of TBX2 in post-mortem brain tissue of AD patients.

Results

Here, we report TBX2 as a transcriptional repressor of ADAM10 gene expression: both, the DNA-binding domain and the repression domain of TBX2 were necessary to effect transcriptional repression of ADAM10 in neuronal SH-SY5Y cells. This regulatory mechanism required HDAC1 as a co-factor of TBX2. Transcriptional repression was mediated by two functional TBX2 binding sites within the core promoter sequence (− 315 to − 286 bp). Analysis of a TBX2 loss-of-function Drosophila model revealed that kuzbanian and kuzbanian-like, orthologs of ADAM10, were derepressed compared to wild type. Vice versa, analysis of cortical brain samples of AD-patients, which showed reduced ADAM10 mRNA levels, revealed a 2.5-fold elevation of TBX2, while TBX3 and TBX21 levels were not affected.

Conclusion

Our results characterize TBX2 as a repressor of ADAM10 gene expression and suggest that this regulatory interaction is conserved across tissues and species.

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Availability of data and materials

The datasets supporting the conclusions of this article are included within the article and its additional files.

Abbreviations

AD:

Alzheimer’s disease

ADAM10:

A disintegrin and metalloproteinase 10

A-beta:

Amyloid-beta

APP:

Amyloid precursor protein

BACE-1:

Beta site APP cleaving enzyme-1

CERAD:

Consortium to establish a registry for Alzheimer’s disease

EST:

Expressed sequence tag

EMSA:

Electrophoretic mobility shift assay

FL:

Full-length

HDAC1:

Histone deacetylase 1

kuz :

Kuzbanian

kul :

Kuzbanian-like

NG2:

Nerve glia antigen 2

NL-1:

Neuroligin-1

Omb :

Optomotor-blind

PPAR-alpha:

Peroxisome proliferator activated receptor-alpha

RB1:

Retinoblastoma 1

Rp49 :

Ribosomal protein 49

SA beta-GAL:

Senescence associated beta-galactosidase

TF:

Transcription factor

TPM:

Transcripts per million

XBP-1:

X-box binding protein-1

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Acknowledgements

This work was supported by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), FKZ01GS08130, 01GS08125 and 01GS08129-5 and by the Alfons Geib Stiftung. We thank K. Hilger, A. Bruns, and S. Schneider (all University Medical Center Mainz, Germany) for technical assistance; we also are grateful to Inka Hoffmann, Fred Eichinger, and Melanie Heyde (University of Mainz, Germany) for preparation of Drosophila wing imaginal discs and to Sven Grösgen (Saarland University, Germany) for experiments regarding human samples; we want to thank Colin Goding (University of Oxford, UK) for murine TBX2 expression constructs and Christian Haass (LMU Munich, Germany) for APP C-terminal antibody 6687. Stock 25706 obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) was used in this study.

Funding

This work was supported by the German Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN) and FKZ01GS08130 and by the Alfons-Geib Stiftung.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Untere Zahlbacher Strasse 8, 55131, Mainz, Germany

    Sven Reinhardt, Florian Schuck, Nicolai Stoye & Kristina Endres

  2. Deutsches Institut für Demenz Prävention (DIDP), Neurodegeneration and Neurobiology, Saarland University, Kirrbergerstrasse 1, 66421, Homburg, Saar, Germany

    Tobias Hartmann & Marcus O. W. Grimm

  3. Experimental Neurology, Saarland University, Kirrbergerstrasse 1, 66421, Homburg, Saar, Germany

    Tobias Hartmann & Marcus O. W. Grimm

  4. Institute of Developmental Biology and Neurobiology, Johannes Gutenberg University, Becherweg 32, 55128, Mainz, Germany

    Gert Pflugfelder

Authors
  1. Sven Reinhardt
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  2. Florian Schuck
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  3. Nicolai Stoye
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  4. Tobias Hartmann
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  5. Marcus O. W. Grimm
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  6. Gert Pflugfelder
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  7. Kristina Endres
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Contributions

KE conceived and coordinated the study, drafted the manuscript, performed experiments with dermal fibroblasts and generated the TBX2 binding site deletion mutant. SR carried out the molecular biology and biochemistry studies, performed analysis on EST profiles, conducted the statistical analysis, and helped to draft the manuscript. FS constructed secreted luciferase reporter vectors and helped to revise the manuscript. NS performed overexpression experiments of HDAC1 to assess effects on ADAM10 and luciferase reporter gene assays for analyzing the TBX2 binding site deletion mutant. MG and TH designed and coordinated studies regarding human brain tissue and revised the manuscript. GP provided expression constructs for human DDK-tagged TBX2 and Drosophila larval samples. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Kristina Endres.

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Ethical approval and consent to participate

All experiments were conducted in accordance to the official regulations for the care and use of laboratory animals and approved by local authorities (University of Mainz, Germany).

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The authors declare that they have no competing interests.

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Reinhardt, S., Schuck, F., Stoye, N. et al. Transcriptional repression of the ectodomain sheddase ADAM10 by TBX2 and potential implication for Alzheimer’s disease. Cell. Mol. Life Sci. 76, 1005–1025 (2019). https://doi.org/10.1007/s00018-018-2998-2

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