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Laminin γ1 chain is essential for the cardiorespiratory and muscular systems

Gawlik, Kinga I. LU ; Bölükbas, Deniz A. LU ; Daoud, Fatima LU ; Peruzzi, Niccolò LU orcid ; Welinder, Ellinor ; Wendt, Trevor S. LU ; Martinez, Marycarmen Arévalo LU ; Tas, Sinem LU ; Holmberg, Johan LU and Gvazava, Nika LU , et al. (2025) In Matrix Biology 141. p.47-66
Abstract

Laminins are basement membrane components that regulate a plethora of biological processes. Despite decades of research, the exact roles of laminins in different tissues and in organogenesis remain to be elucidated. Here, we investigated the function of laminin γ1 chain in heart, lung and other tissues by generating a mouse that lacks laminin γ1 in cells expressing SM22α (Tagln) (LMγ1 flox/SM22α Cre mouse, referred to as LMγ1KO). Laminin γ1 deletion led to basement membrane disruption around cardiomyocytes, smooth muscle cells, alveolar cells and skeletal muscle. This, in turn, led to perinatal death of conditional LMγ1KO mice. Synchrotron-based imaging revealed developmental heart abnormalities: ventricular and atrioventricular septal... (More)

Laminins are basement membrane components that regulate a plethora of biological processes. Despite decades of research, the exact roles of laminins in different tissues and in organogenesis remain to be elucidated. Here, we investigated the function of laminin γ1 chain in heart, lung and other tissues by generating a mouse that lacks laminin γ1 in cells expressing SM22α (Tagln) (LMγ1 flox/SM22α Cre mouse, referred to as LMγ1KO). Laminin γ1 deletion led to basement membrane disruption around cardiomyocytes, smooth muscle cells, alveolar cells and skeletal muscle. This, in turn, led to perinatal death of conditional LMγ1KO mice. Synchrotron-based imaging revealed developmental heart abnormalities: ventricular and atrioventricular septal defects. Lung tissue from embryos and newborns showed impaired alveolization and this defect was not reversed ex vivo. We also created adult inducible laminin γ1 knockout mice (iLMγ1KO) with targeted knockdown in all tissues, and they exhibited decreased contractility of smooth muscle in colonic and arterial tissue. Finally, both LMγ1KO neonates and iLMγ1KO adults displayed severe dystrophic features in skeletal muscle. In summary, our study reveals novel roles for laminin γ1 chain and basement membranes in heart, lung, skeletal and smooth muscle. Compromising basement membranes around various cell types expressing SM22α during embryonic development did not impair early organogenesis of lung, heart and skeletal muscle, but rather disturbed late developmental events in these tissues. Our results could help to understand clinical implications for patients with laminin α2 chain mutations (muscular dystrophy) and laminin α4 mutations (cardiomyopathy), but also for patients with congenital heart disease and lung diseases.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Basement membrane, Cardiomyocyte, Collagen IV, Congenital heart disease, Laminin, Lung development, Smooth muscle cell
in
Matrix Biology
volume
141
pages
20 pages
publisher
Elsevier
external identifiers
  • pmid:40854378
  • scopus:105014993027
ISSN
0945-053X
DOI
10.1016/j.matbio.2025.08.006
language
English
LU publication?
yes
id
ba66e517-ce0e-4c6a-9d7c-6795c26d5637
date added to LUP
2025-10-03 14:02:02
date last changed
2025-10-17 15:56:25
@article{ba66e517-ce0e-4c6a-9d7c-6795c26d5637,
  abstract     = {{<p>Laminins are basement membrane components that regulate a plethora of biological processes. Despite decades of research, the exact roles of laminins in different tissues and in organogenesis remain to be elucidated. Here, we investigated the function of laminin γ1 chain in heart, lung and other tissues by generating a mouse that lacks laminin γ1 in cells expressing SM22α (Tagln) (LMγ1 flox/SM22α Cre mouse, referred to as LMγ1KO). Laminin γ1 deletion led to basement membrane disruption around cardiomyocytes, smooth muscle cells, alveolar cells and skeletal muscle. This, in turn, led to perinatal death of conditional LMγ1KO mice. Synchrotron-based imaging revealed developmental heart abnormalities: ventricular and atrioventricular septal defects. Lung tissue from embryos and newborns showed impaired alveolization and this defect was not reversed ex vivo. We also created adult inducible laminin γ1 knockout mice (iLMγ1KO) with targeted knockdown in all tissues, and they exhibited decreased contractility of smooth muscle in colonic and arterial tissue. Finally, both LMγ1KO neonates and iLMγ1KO adults displayed severe dystrophic features in skeletal muscle. In summary, our study reveals novel roles for laminin γ1 chain and basement membranes in heart, lung, skeletal and smooth muscle. Compromising basement membranes around various cell types expressing SM22α during embryonic development did not impair early organogenesis of lung, heart and skeletal muscle, but rather disturbed late developmental events in these tissues. Our results could help to understand clinical implications for patients with laminin α2 chain mutations (muscular dystrophy) and laminin α4 mutations (cardiomyopathy), but also for patients with congenital heart disease and lung diseases.</p>}},
  author       = {{Gawlik, Kinga I. and Bölükbas, Deniz A. and Daoud, Fatima and Peruzzi, Niccolò and Welinder, Ellinor and Wendt, Trevor S. and Martinez, Marycarmen Arévalo and Tas, Sinem and Holmberg, Johan and Gvazava, Nika and Ansar, Saema and Albinsson, Sebastian and Wagner, Darcy and Swärd, Karl and Tran-Lundmark, Karin and Durbeej, Madeleine}},
  issn         = {{0945-053X}},
  keywords     = {{Basement membrane; Cardiomyocyte; Collagen IV; Congenital heart disease; Laminin; Lung development; Smooth muscle cell}},
  language     = {{eng}},
  pages        = {{47--66}},
  publisher    = {{Elsevier}},
  series       = {{Matrix Biology}},
  title        = {{Laminin γ1 chain is essential for the cardiorespiratory and muscular systems}},
  url          = {{http://dx.doi.org/10.1016/j.matbio.2025.08.006}},
  doi          = {{10.1016/j.matbio.2025.08.006}},
  volume       = {{141}},
  year         = {{2025}},
}