A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations.

A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations.

Science advances (2022-05-19)

Ranjay Jayadev, Mychel R P T Morais, Jamie M Ellingford, Sandhya Srinivasan, Richard W Naylor, Craig Lawless, Anna S Li, Jack F Ingham, Eric Hastie, Qiuyi Chi, Maryline Fresquet, Nikki-Maria Koudis, Huw B Thomas, Raymond T O'Keefe, Emily Williams, Antony Adamson, Helen M Stuart, Siddharth Banka, Damian Smedley, David R Sherwood, Rachel Lennon

PMID35584218

ABSTRACT

Basement membranes (BMs) are ubiquitous extracellular matrices whose composition remains elusive, limiting our understanding of BM regulation and function. By developing a bioinformatic and in vivo discovery pipeline, we define a network of 222 human proteins and their animal orthologs localized to BMs. Network analysis and screening in C. elegans and zebrafish uncovered BM regulators, including ADAMTS, ROBO, and TGFβ. More than 100 BM network genes associate with human phenotypes, and by screening 63,039 genomes from families with rare disorders, we found loss-of-function variants in LAMA5, MPZL2, and MATN2 and show that they regulate BM composition and function. This cross-disciplinary study establishes the immense complexity of BMs and their impact on in human health.

MATERIALS

Product Number

Brand

Product Description

616461

Sigma-Aldrich

TGF-β RI Kinase Inhibitor VI, SB431542, TGF-β RI Kinase Inhibitor VI, SB431542, CAS 301836-41-9, is a cell-permeable inhibitor of SMAD2 phosphorylation. Inhibits the activity of ALK4 and ALK5 (IC₅₀ = 140 nM and 94 nM, respectively).