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RIPK4 regulates cell-cell adhesion in epidermal development and homeostasis
Paola Fortugno1,2, Rosanna Monetta1, Manuel Belli3
1Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
Human Molecular Genetics
|February 27, 2022
Summary
Novel mutations in receptor-interacting protein kinase 4 (RIPK4) disrupt skin development, affecting cell adhesion and differentiation. This research uncovers RIPK4
Area of Science:
- Cell Biology
- Developmental Biology
- Genetics
Background:
- Epidermal development relies on balanced cell proliferation and differentiation.
- Disruptions lead to disorders like ectodermal dysplasias (EDs) and cancer.
- Novel RIPK4 mutations were identified in siblings with a rare ED.
Purpose of the Study:
- To investigate the functional impact of two new RIPK4 missense mutations.
- To understand RIPK4's role in epithelial differentiation and cell adhesion.
- To elucidate the molecular mechanisms underlying a specific autosomal recessive ED.
Main Methods:
- Functional analysis of RIPK4 mutations in patient-derived cells.
- Assessment of epithelial differentiation and cell adhesion markers.
- Investigation of PVRL4/nectin-4 expression and its regulation by IRF6.
- Analysis of desmosome structure and components.
Main Results:
- Mutant RIPK4 impairs epithelial differentiation and cell adhesion.
- RIPK4 mutations lead to reduced PVRL4/nectin-4 expression.
- PVRL4 is transcriptionally regulated by IRF6, a RIPK4 target.
- Defective RIPK4 alters desmosome morphology via plakophilin-1 and desmoplakin.
Conclusions:
- RIPK4 kinase activity is crucial for the p63-IRF6 regulatory pathway.
- This pathway controls the proliferation-differentiation balance and cell adhesion in ectoderm.
- Dysfunctional RIPK4 has implications for ectodermal development and cancer pathogenesis.
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