Mitogen-Activated Protein Kinase Kinase Kinase 1 Overexpression Disrupts Development of the Ocular Surface Epithelium

Mitogen-Activated Protein Kinase Kinase Kinase 1 Overexpression Disrupts Development of the Ocular Surface Epithelium

Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) is a key signaling molecule essential for eyelid closure during embryogenesis. In mice, <i>Map3k1</i> knockout leads to a fully penetrant eye-open at birth (EOB) phenotype due to disrupted MAPK signaling, abnormal epithelial diffe...

Full description

Saved in:
Bibliographic Details
Main Authors: Maureen Mongan, Bo Xiao, Antonius Christianto, Yueh-Chiang Hu, Ying Xia
Format: Article
Language:English
Published: MDPI AG 2025-06-01
Series:Cells
Subjects:
MAP3K1 gain-of-function
ocular surface epithelium
eyelid closure
epithelial morphogenesis
Online Access:https://www.mdpi.com/2073-4409/14/12/894
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) is a key signaling molecule essential for eyelid closure during embryogenesis. In mice, <i>Map3k1</i> knockout leads to a fully penetrant eye-open at birth (EOB) phenotype due to disrupted MAPK signaling, abnormal epithelial differentiation, and morphogenesis. To further explore the roles of MAP3K1 in ocular development, we generated a Cre-inducible gain-of-function transgenic mouse, designated as <i>Map3k1<sup>TG</sup></i>, and crossed it with Lens epithelial (<i>Le)-Cre</i> mice to drive MAP3K1 overexpression in developing ocular surface epithelium (OSE). <i>Map3k1<sup>TG</sup></i>;<i>Le-Cre</i> embryos exhibited ocular defects including premature eyelid closure, lens degeneration, and corneal edema. While corneal epithelial differentiation remained intact, the lens epithelium degenerated with lens formation compromised. Eyelid epithelium was markedly thickened, containing cells with aberrant keratin (K)14/K10 co-expression. Genetic rescue experiments revealed that <i>Map3k1<sup>TG</sup></i>;<i>Le-Cre</i> restored eyelid closure in <i>Map3k1</i> knockout mice, whereas MAP3K1 deficiency attenuated the epithelial thickening caused by transgene expression. Mechanistically, MAP3K1 overexpression enhanced c-Jun phosphorylation in vivo and activated JNK-c-Jun, WNT, TGFβ, and Notch signaling and promoted keratinocyte proliferation and migration in vitro. These findings highlight a dose-sensitive role for MAP3K1 in regulating epithelial proliferation, differentiation, and morphogenesis during eyelid development.
ISSN:2073-4409

Similar Items