A multifunction murine Col4a1 allele reveals potential gene therapy parameters for Gould syndrome DOI
Mao Mao, Yoshihiro Ishikawa, Cassandre Labelle‐Dumais

et al.

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(6)

Published: March 21, 2025

Basement membranes (BMs) are specialized extracellular matrix (ECM) structures essential for organ morphogenesis, architecture, and function. BM composition properties vary between tissues, developmental stages, disease states, there is only a rudimentary understanding of dynamics. Here, we introduce versatile mouse model carrying multifunctional dual-color fluorescence tagged allele with knockout potential the fundamental component type IV collagen alpha 1 (COL4A1). This enables characterization cell type- time-specific contributions to BMs generation conditional Col4a1 null allele. We demonstrate utility this unique genetic resource in providing clinically relevant insights individuals Gould syndrome – multisystem disorder caused by COL4A1 COL4A2 mutations. show active turnover postnatal cerebrovascular BMs, identifying interventional window manifestations associated syndrome. also that heterozygous deletion significantly less pathogenic than dominant missense mutations, which has important implications gene therapy.

Language: Английский

Skeletal pathology in mouse models of Gould syndrome is partially alleviated by genetically reducing TGFβ signaling DOI Creative Commons
Cassandre Labelle‐Dumais, Courtney M. Mazur, Serra Kaya

et al.

Matrix Biology, Journal Year: 2024, Volume and Issue: 133, P. 1 - 13

Published: Aug. 6, 2024

Skeletal defects are hallmark features of many extracellular matrix (ECM) and collagen-related disorders. However, a biological function in bone has never been defined for the highly evolutionarily conserved type IV collagen. Collagen alpha 1 (COL4A1) 2 (COL4A2) form α1α1α2 (IV) heterotrimers that represent fundamental basement membrane constituent present every organ body, including skeleton. COL4A1 COL4A2 mutations cause Gould syndrome, variable clinically heterogenous multisystem disorder generally characterized by presence cerebrovascular disease with ocular, renal, muscular manifestations. We have previously identified elevated TGFβ signaling as pathological insult resulting from Col4a1 demonstrated reducing ameliorate ocular phenotypes mutant mouse models syndrome. In this study, we describe first characterization skeletal mice include developmental delay osteogenesis structural, biomechanical vascular alterations mature bones. Using distinct models, show allelic heterogeneity influences presentation pathology mutations. Importantly, found target gene expression is developing bones genetically partially ameliorates Collectively, these findings identify novel unsuspected role collagen biology, expand spectrum manifestations associated syndrome to abnormalities, implicate pathogenesis mice.

Language: Английский

Citations

5
Discovery of Dual ROCK1/2 Inhibitors from Nocardiopsis sp. under Metal Stress DOI

Thinh T. M. Bui,

Hyejin Ko,

Soohyun Um

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Rho-associated protein kinase (ROCK) inhibitors are promising therapeutic agents for reducing elevated intraocular pressure in patients with glaucoma. We explored new ROCK derived from bioactive metabolites produced by microbes, specifically cryptic Nocardiopsis sp. MCY7, using a liquid chromatography-mass spectrometry-based chemical analysis approach integrated metal stress-driven isolation. This strategy led to the identification of two previously undescribed linear peptides, nocarnickelamides A and B (1 2), an unreported cittilin derivative, C (3). The planar structures 1-3 were elucidated UV spectroscopy, high-resolution mass spectrometry, nuclear magnetic resonance. absolute configurations 1 2 assigned advanced Marfey's method. Biological assays demonstrated that 2) exhibited dual inhibitory activity against ROCK1 (IC50 29.8 14.9 μM, respectively) ROCK2 27.0 21.9 respectively), molecular simulations suggesting binding ATP-binding site. In human trabecular meshwork cells, significantly inhibited activation ROCK-regulated cytoskeletal contraction markers such as myosin light chain. Nocarnickelamide (2) is novel ROCK1/2 inhibitor potential pharmacophore designing reduce

Language: Английский

Citations

0
A multifunction murine Col4a1 allele reveals potential gene therapy parameters for Gould syndrome DOI
Mao Mao, Yoshihiro Ishikawa, Cassandre Labelle‐Dumais

et al.

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(6)

Published: March 21, 2025

Basement membranes (BMs) are specialized extracellular matrix (ECM) structures essential for organ morphogenesis, architecture, and function. BM composition properties vary between tissues, developmental stages, disease states, there is only a rudimentary understanding of dynamics. Here, we introduce versatile mouse model carrying multifunctional dual-color fluorescence tagged allele with knockout potential the fundamental component type IV collagen alpha 1 (COL4A1). This enables characterization cell type- time-specific contributions to BMs generation conditional Col4a1 null allele. We demonstrate utility this unique genetic resource in providing clinically relevant insights individuals Gould syndrome – multisystem disorder caused by COL4A1 COL4A2 mutations. show active turnover postnatal cerebrovascular BMs, identifying interventional window manifestations associated syndrome. also that heterozygous deletion significantly less pathogenic than dominant missense mutations, which has important implications gene therapy.

Language: Английский

Citations

0