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

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=11

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1169962

DOI=10.3389/fcell.2023.1169962

ISSN=2296-634X

ABSTRACT=<p>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 <italic>FIBRONECTIN 1</italic> (<italic>FN1</italic>), the <italic>VASCULAR CELL ADHESION MOLECULE 1</italic> (<italic>VCAM1</italic>), as well as their receptor <italic>INTEGRIN α4β1</italic> (<italic>ITGA4B1</italic>) in HUVEC cells. Importantly, reducing the levels of <italic>ITGA4, FN1</italic>, and <italic>VCAM1</italic> 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.</p>