Functional assessment of CELSR1 variants associated with human developmental defects.
4 affiliations
- 1Department of Dermatology Penn State College of Medicine, Hershey, PA, United States.
- 2Biomedical Sciences Graduate Program Penn State College of Medicine, Hershey, PA, United States.
- 3Medical Scientist Training Program, Penn State College of Medicine, Hershey, PA, United States.
- 4Department of Cell and Biological Systems Penn State College of Medicine, Hershey, PA, United States.
Abstract
During development, collective and oriented cell behaviors that drive organ formation and tissue patterning require coordination among neighboring cells governed by the highly conserved planar cell polarity (PCP) pathway. Deficiencies in PCP gene function result in severe developmental defects in model systems from flies to mice, while PCP gene mutations are associated with human birth defects impacting the neural tube and heart. Atypical cadherin Celsr1 engages in cell-cell adhesion to coordinate the asymmetric localization of Fz6 and Vangl2 to opposing sides of the PCP junction between neighboring cells. However, whether CELSR1 genetic variations disrupt function or contribute to disease pathogenesis remains poorly understood. Using cell-based assays for Celsr1 function, along with in silico modeling, we test a cohort of 17 Celsr1 mutations previously identified in patients with neural tube and congenital heart defects. In junctional enrichment assays, we find 13 variants displayed altered enrichment at cell borders relative to WT, including both loss- and gain-of-function behaviors. Further analysis of select Celsr1 mutations revealed defects in membrane mobility and perturbed co-recruitment of PCP protein Fz6. Our findings link Celsr1 mutations associated with human birth defects to functional defects in adhesion and PCP. In addition, our approach supports a framework for evaluating PCP function alongside genomics and in silico predictions toward understanding the pathophysiology impacts of genetic variations associated with human developmental disorders and gaining insight into Celsr1 function during development.
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BibTeX
@article{stenson2026functional,
title = {{Functional assessment of CELSR1 variants associated with human developmental defects.}},
author = {Jazmin M Stenson and William Giang and Sarah G Latario and Courtney L Williams and Valerie Trujillo Adorno and Congzhou M Sha and Sara N Stahley},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1818587},
url = {https://europepmc.org/article/MED/42923285},
note = {CC BY},
}
RIS
TY - JOUR
TI - Functional assessment of CELSR1 variants associated with human developmental defects.
AU - Jazmin M Stenson
AU - William Giang
AU - Sarah G Latario
AU - Courtney L Williams
AU - Valerie Trujillo Adorno
AU - Congzhou M Sha
AU - Sara N Stahley
PY - 2026
DA - 2026/10/08
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1818587
UR - https://europepmc.org/article/MED/42923285
AB - During development, collective and oriented cell behaviors that drive organ formation and tissue patterning require coordination among neighboring cells governed by the highly conserved planar cell polarity (PCP) pathway. Deficiencies in PCP gene function result in severe developmental defects in model systems from flies to mice, while PCP gene mutations are associated with human birth defects impacting the neural tube and heart. Atypical cadherin Celsr1 engages in cell-cell adhesion to coordinate the asymmetric localization of Fz6 and Vangl2 to opposing sides of the PCP junction between neighboring cells. However, whether CELSR1 genetic variations disrupt function or contribute to disease pathogenesis remains poorly understood. Using cell-based assays for Celsr1 function, along with in silico modeling, we test a cohort of 17 Celsr1 mutations previously identified in patients with neural tube and congenital heart defects. In junctional enrichment assays, we find 13 variants displayed altered enrichment at cell borders relative to WT, including both loss- and gain-of-function behaviors. Further analysis of select Celsr1 mutations revealed defects in membrane mobility and perturbed co-recruitment of PCP protein Fz6. Our findings link Celsr1 mutations associated with human birth defects to functional defects in adhesion and PCP. In addition, our approach supports a framework for evaluating PCP function alongside genomics and in silico predictions toward understanding the pathophysiology impacts of genetic variations associated with human developmental disorders and gaining insight into Celsr1 function during development.
SN - 2296-634X
ER -