Laminin N‐terminus α31 expression during development is lethal and causes widespread tissue‐specific defects in a transgenic mouse model

Sugden, Conor J; Iorio, Valentina Di; Troughton, Lee D.; Liu, Ke; Morais, Mychel Raony Paiva Teixeira; Lennon, Rachel; Bou‐Gharios, George; Hamill, Kevin J.

doi:10.1096/fj.202002588rrr

Cited by 3 publications

(1 citation statement)

References 108 publications

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“…Twenty years have passed since Snead et al identified a novel cell population, integral to the PHM, for which they proposed the term ‘laminocyte’. This name was chosen to highlight both its basement membrane association (of which type IV collagen and laminins are essential structural components) and additionally the laminar pattern of their array entirely within the plane of the detached PHM but absent from the main body of the vitreous gel itself [ 13 , 65 ]. Decades of earlier publications reported the presence of vitreal cells associated with the vitreoretinal interface but failed to classify them morphologically or via immunohistochemistry [ 66 , 67 ].…”

Section: The Laminocytementioning

confidence: 99%

A Novel Transcriptome Approach to the Investigation of the Molecular Pathology of Vitreous and Retinal Detachment

Maranian

Snead²

2022

Genes

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Retinal detachment (RD) is one of the most common, sight-threatening ocular conditions requiring emergency intervention. Posterior vitreous detachment (PVD) occurs in the majority of an aging population whereby the vitreous body separates from the retina. It is well established that PVD is the common precursor to the most common forms of RD; however, it remains unknown why in most individuals PVD will cause no/few complications (physiological PVD) but in a small percentage will cause retinal tears and detachment (pathological PVD). Despite over 100 years of scientific research, the anatomical definitions of PVD and its pathogenesis remain controversial. Recent research has identified a novel cell population (laminocyte), present at significantly higher numbers in pathological PVD when compared to physiological PVD. We review and summarise the seven distinct clinical sub-groups of retinal breaks and focus on the role of the laminocyte in those secondary to PVD and the transcriptomic profile of this unique cell. Provisional whole transcriptome analysis using bulk RNA-Seq shows marked differentially expressed genes when comparing physiological PVD with PVD associated with RD. The limitations of bulk RNA-Seq are considered and the potential to address these using spatial transcriptomics are discussed. Understanding the pathogenesis of PVD-related retinal tears will provide a baseline for the development of novel therapeutic targets and prophylactic treatments.

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Section: The Laminocytementioning

confidence: 99%

A Novel Transcriptome Approach to the Investigation of the Molecular Pathology of Vitreous and Retinal Detachment

Maranian

Snead²

2022

Genes

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Laminin N-terminus (LaNt) proteins, laminins and basement membrane regulation

Chavda

Sari

Asiri

et al. 2022

Biochemical Society Transactions

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Basement membranes (BMs) are structured regions of the extracellular matrix that provide multiple functions including physical support and acting as a barrier, as a repository for nutrients and growth factors, and as biophysical signalling hubs. At the core of all BMs is the laminin (LM) family of proteins. These large heterotrimeric glycoproteins are essential for tissue integrity, and differences between LM family members represent a key nexus in dictating context and tissue-specific functions. These variations reflect genetic diversity within the family, which allows for multiple structurally and functionally distinct heterotrimers to be produced, each with different architectures and affinities for other matrix proteins and cell surface receptors. The ratios of these LM isoforms also influence the biophysical properties of a BM owing to differences in their relative ability to form polymers or networks. Intriguingly, the LM superfamily is further diversified through the related netrin family of proteins and through alternative splicing leading to the generation of non-LM short proteins known as the laminin N-terminus (LaNt) domain proteins. Both the netrins and LaNt proteins contain structural domains involved in LM-to-LM interaction and network assembly. Emerging findings indicate that one netrin and at least one LaNt protein can potently influence the structure and function of BMs, disrupting the networks, changing physical properties, and thereby influencing tissue function. These findings are altering the way that we think about LM polymerisation and, in the case of the LaNt proteins, suggest a hitherto unappreciated form of LM self-regulation.

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Laminin N‐terminus α31 expression during development is lethal and causes widespread tissue‐specific defects in a transgenic mouse model

et al. 2022

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Laminins (LMs) are essential components of all basement membranes where they regulate an extensive array of tissue functions. Alternative splicing from the laminin α3 gene produces a non-laminin but netrin-like protein, Laminin N terminus α31 (LaNt α31). LaNt α31 is widely expressed in intact tissue and is upregulated in epithelial cancers and during wound healing. In vitro functional studies have shown that LaNt α31 can influence numerous aspects of epithelial cell behavior via modifying matrix organization, suggesting a new model of laminin auto-regulation. However, the function of this protein has not been established in vivo. Here, a mouse transgenic line was generated using the ubiquitin C promoter to drive inducible expression of LaNt α31. When expression was induced at embryonic day 15.5, LaNt α31 transgenic animals were not viable at birth, exhibiting localized regions of erythema. Histologically, the most striking defect was widespread evidence of extravascular bleeding across multiple tissues. Additionally, LaNt α31 transgene expressing animals exhibited kidney epithelial detachment, tubular dilation, disruption of the epidermal basal cell layer and of the hair follicle outer root sheath, and ~50% reduction of cell numbers in the liver, associated with depletion of hematopoietic erythrocytic foci. These findings provide the first in vivo evidence that LaNt α31 can influence tissue morphogenesis.

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Laminin N‐terminus α31 expression during development is lethal and causes widespread tissue‐specific defects in a transgenic mouse model

Cited by 3 publications

References 108 publications

A Novel Transcriptome Approach to the Investigation of the Molecular Pathology of Vitreous and Retinal Detachment

A Novel Transcriptome Approach to the Investigation of the Molecular Pathology of Vitreous and Retinal Detachment

Laminin N-terminus (LaNt) proteins, laminins and basement membrane regulation

Laminin N‐terminus α31 expression during development is lethal and causes widespread tissue‐specific defects in a transgenic mouse model

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