Loss of TDP-43 causes ectopic endothelial sprouting and migration defects through increased fibronectin, vcam 1 and integrin α4/β1

Katrin Hipke; Bettina Pitter; Alexander Hruscha; Frauke van Bebber; Miha Modic; Vikas Bansal; Sebastian A Lewandowski; Denise Orozco; Dieter Edbauer; Stefan Bonn; Christian Haass; Ulrich Pohl; Eloi Montanez; Bettina Schmid

doi:10.3389/fcell.2023.1169962

Loss of TDP-43 causes ectopic endothelial sprouting and migration defects through increased fibronectin, vcam 1 and integrin α4/β1

Front Cell Dev Biol. 2023 Jun 13:11:1169962. doi: 10.3389/fcell.2023.1169962. eCollection 2023.

Authors

Katrin Hipke^{1

2}, Bettina Pitter³, Alexander Hruscha¹, Frauke van Bebber¹, Miha Modic^{4

5

6}, Vikas Bansal⁷, Sebastian A Lewandowski⁸, Denise Orozco¹, Dieter Edbauer^{1

2

9}, Stefan Bonn¹⁰, Christian Haass^{1

2

9}, Ulrich Pohl^{2

3

9

11}, Eloi Montanez¹², Bettina Schmid^{1

2}

Affiliations

¹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
² Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
³ Walter Brendel Center, Biomedical Center, Ludwig-Maximilians-University Munich, Munich, Germany.
⁴ The Francis Crick Institute, London, United Kingdom.
⁵ Dementia Research Institute at KCL, London, United Kingdom.
⁶ National Institute of Chemistry, Ljubljana, Slovenia.
⁷ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁸ Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institute, Stockholm, Sweden.
⁹ Biomedical Center, Ludwig-Maximilians-University Munich, Munich, Germany.
¹⁰ Institute of Medical Systems Biology, Center for Biomedical AI (bAIome), Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹¹ DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
¹² Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona and Bellvitge Biomedical Research Institute, Barcelona, Spain.

Abstract

Aggregation of the Tar DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia and likely contributes to disease by loss of nuclear function. Analysis of TDP-43 function in knockout zebrafish identified an endothelial directional migration and hypersprouting phenotype during development prior lethality. In human umbilical vein cells (HUVEC) the loss of TDP-43 leads to hyperbranching. We identified elevated expression of FIBRONECTIN 1 (FN1), the VASCULAR CELL ADHESION MOLECULE 1 (VCAM1), as well as their receptor INTEGRIN α4β1 (ITGA4B1) in HUVEC cells. Importantly, reducing the levels of ITGA4, FN1, and VCAM1 homologues in the TDP-43 loss-of-function zebrafish rescues the angiogenic defects indicating the conservation of human and zebrafish TDP-43 function during angiogenesis. Our study identifies a novel pathway regulated by TDP-43 important for angiogenesis during development.

Keywords: ALS; TDP-43; angiogenesis; neurodegeneration; zebrafish.

Grants and funding

This work was supported by the Helmholtz cross-program topic “Metabolic Dysfunction” and “AMPro”, the Thierry Latran foundation, the Deutsche Forschungsgemeinschaft (DFG) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy), the Hans und Ilse Breuer foundation, and IMPRS. SAL is supported by the Swedish FTD initiative, Olle Engkvist Byggmästare Foundation and Åhlén Foundation (mA2/h17). EM is supportd by the DFG grant MO2562/1-2. and by the Spanish Ministry of Science, Innovation and Universities (PID 2019-108902 GB-I00).