The 4E-BP1 deletion modestly mitigates mTORC1-deficient epidermal barrier defects

Area of Science:

• Cell Biology
• Developmental Biology
• Genetics

Background:

• Mammalian target of rapamycin (mTOR) signaling is crucial for epidermal development.
• The precise downstream effectors of mTOR in skin morphogenesis are not fully understood.
• 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) is a key mTORC1 inhibitor of cap-dependent translation with an unclear role in epidermal development.

Purpose of the Study:

• To investigate the role of 4E-BP1 in epidermal morphogenesis.
• To determine the impact of 4E-BP1 loss on skin barrier defects caused by mTORC1 inactivation.
• To elucidate the downstream mechanisms of mTORC1 signaling in skin development.

Main Methods:

• Generated 4E-BP1 knockout (Eif4ebp1-/-) mice using CRISPR/Cas9.
• Created double-knockout (dKO) mice by crossing Eif4ebp1-/- mice with epidermal-specific Raptor knockout (RapEKO) mice.
• Assessed skin barrier function using toluidine blue assays and analyzed epidermal morphology via histology.

Main Results:

• Both RapEKO and dKO neonates exhibited fragile skin, weight loss, and neonatal lethality.
• dKO mice showed a partial restoration of skin barrier function compared to RapEKO mice.
• Histological analysis revealed improved, though irregular, cornification and slightly increased epidermal thickness in dKO mice, with partially restored differentiation markers despite impaired proliferation.

Conclusions:

• 4E-BP1 deletion partially rescues epidermal differentiation and barrier defects resulting from mTORC1 inactivation.
• 4E-BP1 is not the major downstream effector of mTORC1 in epidermal morphogenesis, as neonatal lethality persists.
• These findings refine our understanding of mTORC1 signaling pathways in skin development.