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

  • Sven Reinhardt
  • Florian Schuck
  • Nicolai Stoye
  • Tobias Hartmann
  • Marcus O. W. Grimm
  • Gert Pflugfelder
  • Kristina EndresEmail author
Original Article

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.

Keywords

ADAM10 Alpha-secretase APP-processing Kuzbanian Omb TBX2 Transcriptional regulation 

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

Notes

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.

Author 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.

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.

Compliance with ethical standards

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).

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

18_2018_2998_MOESM1_ESM.pdf (76 kb)
Supplementary material 1 (PDF 76 kb)
18_2018_2998_MOESM2_ESM.pdf (75 kb)
Supplementary material 2 (PDF 75 kb)
18_2018_2998_MOESM3_ESM.pdf (90 kb)
Supplementary material 3 (PDF 90 kb)
18_2018_2998_MOESM4_ESM.pdf (85 kb)
Supplementary material 4 (PDF 84 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Psychiatry and PsychotherapyUniversity Medical Center of the Johannes Gutenberg University MainzMainzGermany
  2. 2.Deutsches Institut für Demenz Prävention (DIDP), Neurodegeneration and NeurobiologySaarland UniversityHomburgGermany
  3. 3.Experimental NeurologySaarland UniversityHomburgGermany
  4. 4.Institute of Developmental Biology and NeurobiologyJohannes Gutenberg UniversityMainzGermany

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