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

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.

Clinical Implications and Molecular Features of Extracellular Matrix Networks in Soft Tissue Sarcomas

“…3B ; ref. 19 ), which further confirms the proteomic results previously obtained from FFPE tissue ( Fig. 1B ).…”

Clinical Implications and Molecular Features of Extracellular Matrix Networks in Soft Tissue Sarcomas

“…3B ; ref. 19 ), which further confirms the proteomic results previously obtained from FFPE tissue ( Fig. 1B ).…”

WormTagDB: a systematic survey of endogenously tagged proteins in Caenorhabditis elegans and roadmap toward the tagged proteome

“… Honda et al 2017 ; Nishida et al 2021 ; Xu et al 2024 ). Collagen-containing extracellular matrix also stands out (25/29, 86.2%), consistent with extensive studies of cuticular collagens, basement-membrane dynamics, and tissue remodeling ( Keeley et al 2020 ; Jayadev et al 2022 ; Adams et al 2023 ; Ragle et al 2025 ). Broader enriched categories include RNA regulation (ribonucleoprotein granule 92/164, 56.0%; regulatory ncRNA-mediated gene silencing 62/217, 28.6%), protein–protein and protein–DNA interactions (protein binding 641/2856, 22.4%; nucleic acid binding 372/1308, 28.4%, DNA-binding transcription factor activity 177/624, 28.4%), and developmental biology terms including cell differentiation (177/453, 39.1%), multicellular development (248/620, 40.0%), larval development (141/345, 40.9%), and neurogenesis (57/107, 54.3%).…”

UNC-6/Netrin promotes both adhesion and directed growth within a single axon

“…To further understand how UNC-6 and UNC-40 regulate axon development, we inserted a GFP tag at the C-terminus of the endogenous unc-40 locus. The resulting animals show UNC-40::GFP fluorescence in the nerve ring and major nerve cords of the worm (VNC and dorsal nerve cord), consistent with a published endogenous UNC-40::mNeonGreen strain (Figure S1C-E) (Jayadev et al, 2022). We next analyzed movies of UNC-40::GFP during PDE axon outgrowth.…”

Clinical Implications and Molecular Features of Extracellular Matrix Networks in Soft Tissue Sarcomas

“…3B ; ref. 19 ), which further confirms the proteomic results previously obtained from FFPE tissue ( Fig. 1B ).…”

WormTagDB: a systematic survey of endogenously tagged proteins in Caenorhabditis elegans and roadmap toward the tagged proteome

“… Honda et al 2017 ; Nishida et al 2021 ; Xu et al 2024 ). Collagen-containing extracellular matrix also stands out (25/29, 86.2%), consistent with extensive studies of cuticular collagens, basement-membrane dynamics, and tissue remodeling ( Keeley et al 2020 ; Jayadev et al 2022 ; Adams et al 2023 ; Ragle et al 2025 ). Broader enriched categories include RNA regulation (ribonucleoprotein granule 92/164, 56.0%; regulatory ncRNA-mediated gene silencing 62/217, 28.6%), protein–protein and protein–DNA interactions (protein binding 641/2856, 22.4%; nucleic acid binding 372/1308, 28.4%, DNA-binding transcription factor activity 177/624, 28.4%), and developmental biology terms including cell differentiation (177/453, 39.1%), multicellular development (248/620, 40.0%), larval development (141/345, 40.9%), and neurogenesis (57/107, 54.3%).…”

UNC-6/Netrin promotes both adhesion and directed growth within a single axon

“…To further understand how UNC-6 and UNC-40 regulate axon development, we inserted a GFP tag at the C-terminus of the endogenous unc-40 locus. The resulting animals show UNC-40::GFP fluorescence in the nerve ring and major nerve cords of the worm (VNC and dorsal nerve cord), consistent with a published endogenous UNC-40::mNeonGreen strain (Figure S1C-E) (Jayadev et al, 2022). We next analyzed movies of UNC-40::GFP during PDE axon outgrowth.…”

Clinical Implications and Molecular Features of Extracellular Matrix Networks in Soft Tissue Sarcomas

“…3B ; ref. 19 ), which further confirms the proteomic results previously obtained from FFPE tissue ( Fig. 1B ).…”

WormTagDB: a systematic survey of endogenously tagged proteins in Caenorhabditis elegans and roadmap toward the tagged proteome

“… Honda et al 2017 ; Nishida et al 2021 ; Xu et al 2024 ). Collagen-containing extracellular matrix also stands out (25/29, 86.2%), consistent with extensive studies of cuticular collagens, basement-membrane dynamics, and tissue remodeling ( Keeley et al 2020 ; Jayadev et al 2022 ; Adams et al 2023 ; Ragle et al 2025 ). Broader enriched categories include RNA regulation (ribonucleoprotein granule 92/164, 56.0%; regulatory ncRNA-mediated gene silencing 62/217, 28.6%), protein–protein and protein–DNA interactions (protein binding 641/2856, 22.4%; nucleic acid binding 372/1308, 28.4%, DNA-binding transcription factor activity 177/624, 28.4%), and developmental biology terms including cell differentiation (177/453, 39.1%), multicellular development (248/620, 40.0%), larval development (141/345, 40.9%), and neurogenesis (57/107, 54.3%).…”

UNC-6/Netrin promotes both adhesion and directed growth within a single axon

“…To further understand how UNC-6 and UNC-40 regulate axon development, we inserted a GFP tag at the C-terminus of the endogenous unc-40 locus. The resulting animals show UNC-40::GFP fluorescence in the nerve ring and major nerve cords of the worm (VNC and dorsal nerve cord), consistent with a published endogenous UNC-40::mNeonGreen strain (Figure S1C-E) (Jayadev et al, 2022). We next analyzed movies of UNC-40::GFP during PDE axon outgrowth.…”