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Novel mouse line with D277N mutation in the <i>Plau</i> gene displays autism spectrum disorder-like traits.

Overview

Authors: Maxim Karagyaur1, Olga Averina2, Kirill Bozov1, Stalik Dzhauari1, Anastasia Priymak1,2, Raushana Khaybullina1, Oleg Permyakov2, Vladimir Popov1, Olga Grigorieva2, Maria Illarionova1, Liliia Shkarina1, Mikhail Gulyaev3, Dmitry Lebedev4, Alexandra Primak1, Petr Sergiev2, Ekaterina Semina1,5, Polina Klimovich1, Larisa Samokhodskaya1, Pavel Malkov1, Yury Pirogov3,4, Boris Tsygankov6, Yuliya Chaika5, Vsevolod Tkachuk1, Elena Neyfeld1,5
  1. Medical Research and Education Institute, Lomonosov Moscow State University, Moscow, Russia
  2. A.N. Belozersky Institute Of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
  3. Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russia
  4. Faculty of Physics, Lomonosov Moscow State University, Moscow, Russia
  5. Scientific Center for Mental Health, Moscow, Russia
  6. Russian University of Medicine of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
Institutions: Lomonosov Moscow State University (Russia); Ministry of Health of the Russian Federation (Russia)
Journal: Frontiers in cell and developmental biology, volume 14, article 1762737
Dates: received 7 December 2025; accepted 1 April 2026; published online 6 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3389/fcell.2026.1762737 · PMID 42170179 · PMCID PMC13187116 · OpenAlex W7160405941
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), autism (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: autism spectrum disorder (ASD), cognitive and behavioral tests, CRISPR/Cas9, elevated plus maze, PLAU gene, rs1243306395, three-chamber social test, urokinase-type plasminogen activator (uPA)
Topic: Protease and Inhibitor Mechanisms (Cancer Research, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Citations: not cited yet (Europe PMC); 64 references in the paper

Abstract

Introduction: Genetic technologies provide an opportunity to study the molecular basis of a wide range of hereditary pathologies, including mental disorders. Reproducing of potentially pathogenic genomic variants in cellular and animal models allows establishing their functional significance and possible mechanisms of involvement in the pathogenesis of certain disorders.

Methods: In this study, a genetic variant of urokinase type plasminogen activator (uPA, gene Plau) was modeled in mice using CRISPR/Cas genome editing tool, enabling a better understanding of the role of this molecule and its associated pathways in brain development. The protease uPA plays an important role in the directed migration of neural progenitors, glial, endothelial and immune cells, it participates in axon guidance and maturation of synaptic connections, activation of growth factors and degradation of the extracellular matrix. To study the contribution of the catalytic function of uPA to brain development, we have created for the first time a mouse line carrying the D277N (rs1243306395) mutation. We assessed social activity, anxiety, memory, problem-solving ability and stress resistance of these mice, as well as histological features of their brains.

Results: Timely and correct functioning of the Plau gene ensures adequate positioning of crucial cellular components in the developing nervous system. According to bioinformatic calculations, the D277N (corresponds to the human single nucleotide variant rs1243306395) substitution that happens due to C-to-T mutation in the murine Plau gene may impair the catalytic activity of the uPA protein. While retaining their ability to find solutions in the escape test, this mouse line is characterized by high levels of anxiety, impaired social behavior, slowed learning dynamics (spatial memory), and impaired adaptation to stressors. This behavioral pattern can potentially be interpreted as autism spectrum disorder Histological analysis of the brain and cerebral cortex in Plau-D277N mice revealed brain volume enlargement and cortical thickening of approximately 10-15% compared to wild-type mice.

Discussion: In this study, we draw attention for the first time to the genomic variant rs1243306395 in the Plau gene as a potential cause of autism spectrum disorder and propose the genetically modified Plau-D277N mouse line as a model object for studying the pathogenesis of this disorder. These models can also be used for the development and testing of promising therapeutic approaches and pharmacological agents.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 24 authors, 8 keywords, 55 references.

Cite

This paper

Karagyaur, M., Averina, O., Bozov, K., Dzhauari, S., Priymak, A., Khaybullina, R., Permyakov, O., Popov, V., Grigorieva, O., Illarionova, M., Shkarina, L., Gulyaev, M., Lebedev, D., Primak, A., Sergiev, P., Semina, E., Klimovich, P., Samokhodskaya, L., Malkov, P., . . . Neyfeld, E. (2026). Novel mouse line with D277N mutation in the <i>Plau</i> gene displays autism spectrum disorder-like traits. Frontiers in cell and developmental biology, 14, 1762737. https://doi.org/10.3389/fcell.2026.1762737

BibTeX

@article{karagyaur2026novel,
author = {Karagyaur, Maxim and Averina, Olga and Bozov, Kirill and Dzhauari, Stalik and Priymak, Anastasia and Khaybullina, Raushana and Permyakov, Oleg and Popov, Vladimir and Grigorieva, Olga and Illarionova, Maria and Shkarina, Liliia and Gulyaev, Mikhail and Lebedev, Dmitry and Primak, Alexandra and Sergiev, Petr and Semina, Ekaterina and Klimovich, Polina and Samokhodskaya, Larisa and Malkov, Pavel and Pirogov, Yury and Tsygankov, Boris and Chaika, Yuliya and Tkachuk, Vsevolod and Neyfeld, Elena},
title = {{Novel mouse line with D277N mutation in the \<i\>Plau\</i\> gene displays autism spectrum disorder-like traits}},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = may,
volume = {14},
pages = {1762737},
publisher = {Frontiers Media SA},
issn = {2296-634X},
doi = {10.3389/fcell.2026.1762737},
url = {https://doi.org/10.3389/fcell.2026.1762737},
pmid = {42170179},
pmcid = {PMC13187116}
}

RIS

TY - JOUR
AU - Karagyaur, Maxim
AU - Averina, Olga
AU - Bozov, Kirill
AU - Dzhauari, Stalik
AU - Priymak, Anastasia
AU - Khaybullina, Raushana
AU - Permyakov, Oleg
AU - Popov, Vladimir
AU - Grigorieva, Olga
AU - Illarionova, Maria
AU - Shkarina, Liliia
AU - Gulyaev, Mikhail
AU - Lebedev, Dmitry
AU - Primak, Alexandra
AU - Sergiev, Petr
AU - Semina, Ekaterina
AU - Klimovich, Polina
AU - Samokhodskaya, Larisa
AU - Malkov, Pavel
AU - Pirogov, Yury
AU - Tsygankov, Boris
AU - Chaika, Yuliya
AU - Tkachuk, Vsevolod
AU - Neyfeld, Elena
TI - Novel mouse line with D277N mutation in the <i>Plau</i> gene displays autism spectrum disorder-like traits
T2 - Frontiers in cell and developmental biology
J2 - Front Cell Dev Biol
PY - 2026
DA - 2026/05/06
VL - 14
SP - 1762737
SN - 2296-634X
PB - Frontiers Media SA
DO - 10.3389/fcell.2026.1762737
UR - https://doi.org/10.3389/fcell.2026.1762737
LA - en
ER -

CSL-JSON

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