Coordinated inhibition of SOX9 and cell cycle progression by microRNA-200 restricts sebaceous gland fate...

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• The microRNA-200 family (miR-200s) is known to inhibit epithelial-to-mesenchymal transition and cell cycle progression in cancer.
• The specific functions of miR-200s in normal epithelial development, particularly in the hair follicle, are not well understood.

Purpose of the Study:

• To investigate the role of miR-200s in hair follicle (HF) development and sebaceous gland (SG) specification.
• To elucidate the molecular mechanisms by which miR-200s regulate cell fate determination in the upper HF.

Main Methods:

• Single-cell and spatial transcriptomic analyses were employed to study gene expression patterns.
• Genome-wide identification of microRNA-200 and SOX9 targets was performed.
• Experimental manipulation of miR-200 expression in the hair follicle was conducted.

Main Results:

• miR-200s are enriched in hair matrix progenitors but absent in the upper HF, where SG and HF stem cells are specified.
• Elevated miR-200 expression in the upper HF inhibits SG fate specification while allowing hair morphogenesis.
• miR-200s target negative regulators of WNT signaling and cell cycle regulators, disrupting the WNT activity/SOX9 balance and compromising SOX9 function.
• SOX9 regulates a network of lipid and fatty acid metabolism genes crucial for SG progenitor differentiation.
• miR-200s block SG specification by inhibiting the SOX9-dependent lipogenic program and restricting cell cycle progression.

Conclusions:

• This study reveals a novel, spatially defined role for miR-200s in restricting epithelial plasticity during hair follicle development.
• miR-200s act by inhibiting a SOX9-driven transcriptional program essential for sebaceous gland formation.
• The findings elucidate a critical regulatory network for sebaceous gland development and highlight the specificity of miR-200 function in normal tissue homeostasis.