Basement membranes (BMs) are specialized extracellular matrix (ECM) structures essential for organ morphogenesis, architecture, and function. BM composition and properties vary between tissues, developmental stages, and disease states, and there is only a rudimentary understanding of BM dynamics. Here, we introduce a versatile mouse model carrying a multifunctional dual-color fluorescence tagged allele with knockout potential for the fundamental BM component type IV collagen alpha 1 (COL4A1). This allele enables the characterization of cell type- and time-specific contributions to BMs and the generation of a conditional Col4a1 null allele. We demonstrate the utility of this unique genetic resource in providing clinically relevant insights for individuals with Gould syndrome – a multisystem disorder caused by COL4A1 and COL4A2 mutations. We show active COL4A1 turnover in postnatal cerebrovascular BMs, identifying a potential interventional window for cerebrovascular manifestations associated with Gould syndrome. We also demonstrate that heterozygous Col4a1 deletion is significantly less pathogenic than dominant Col4a1 missense mutations, which has important implications for gene therapy.
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April 25 2025
A multifunction murine Col4a1 allele reveals potential gene therapy parameters for Gould syndrome
Mao Mao
,
Mao Mao
(Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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Yoshihiro Ishikawa
,
Yoshihiro Ishikawa
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Validation, Visualization, Writing - review & editing)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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Cassandre Labelle-Dumais
,
Cassandre Labelle-Dumais
(Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing - review & editing)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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Xiaowei Wang
,
Xiaowei Wang
(Investigation)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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Yien-Ming Kuo
,
Yien-Ming Kuo
(Investigation)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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Uma B. Gaffney
,
Uma B. Gaffney
(Investigation)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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Megan E. Smith
,
Megan E. Smith
(Investigation)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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Carlie N. Abdala
,
Carlie N. Abdala
(Investigation)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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Matthew D. Lebedev
,
Matthew D. Lebedev
(Investigation)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
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William J. Paradee
,
William J. Paradee
(Conceptualization, Methodology)
2Genome Editing Core Facility,
University of Iowa
, Iowa City, IA, USA
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Douglas B. Gould
(Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing)
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
3Department of Anatomy,
Institute for Human Genetics, Cardiovascular Research Institute, and Bakar Aging Research Institute, University of California San Francisco
, San Francisco, CA, USA
Correspondence to Douglas B. Gould: [email protected]
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Mao Mao
Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
Yoshihiro Ishikawa
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Validation, Visualization, Writing - review & editing
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
Cassandre Labelle-Dumais
Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing - review & editing
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
Xiaowei Wang
Investigation
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
Yien-Ming Kuo
Investigation
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
Uma B. Gaffney
Investigation
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
Megan E. Smith
Investigation
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
Carlie N. Abdala
Investigation
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
Matthew D. Lebedev
Investigation
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
William J. Paradee
Conceptualization, Methodology
2Genome Editing Core Facility,
University of Iowa
, Iowa City, IA, USA
Douglas B. Gould
Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing
1Department of Ophthalmology,
University of California San Francisco
, San Francisco, CA, USA
3Department of Anatomy,
Institute for Human Genetics, Cardiovascular Research Institute, and Bakar Aging Research Institute, University of California San Francisco
, San Francisco, CA, USA
Correspondence to Douglas B. Gould: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
September 27 2024
Revision Received:
February 22 2025
Accepted:
March 20 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Institutes of Health
- Award Id(s): 1R21NS133610,1RF1NS128217
Funder(s):
National Institue of Neurological Disease and Stroke
Funder(s):
All May See Foundation
Funder(s):
National Eye Institute
- Award Id(s): P30 EY002162
Funder(s):
Research to Prevent Blindness
© 2025 Mao et al.
2025
Mao et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (6): e202409153.
Article history
Received:
September 27 2024
Revision Received:
February 22 2025
Accepted:
March 20 2025
Citation
Mao Mao, Yoshihiro Ishikawa, Cassandre Labelle-Dumais, Xiaowei Wang, Yien-Ming Kuo, Uma B. Gaffney, Megan E. Smith, Carlie N. Abdala, Matthew D. Lebedev, William J. Paradee, Douglas B. Gould; A multifunction murine Col4a1 allele reveals potential gene therapy parameters for Gould syndrome. J Cell Biol 2 June 2025; 224 (6): e202409153. doi: https://doi.org/10.1083/jcb.202409153
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