[Genetic dissection of retinoic acid function in epidermis physiology]

Area of Science:

• Molecular biology
• Dermatology
• Genetics

Context:

• Retinoic acid (RA) is a key signaling molecule in skin physiology, acting through nuclear receptors RARs and RXRs.
• RAR/RXR heterodimers regulate gene transcription, influencing various cellular processes.
• RXR nuclear receptors also form heterodimers with other receptors, like the vitamin D3 receptor (VDR), indicating broader signaling roles.

Purpose:

• To investigate the specific roles of Retinoid Acid Receptor (RAR) and Retinoid X Receptor (RXR) subtypes in skin physiology.
• To elucidate the function of RXRalpha in adult skin using conditional somatic mutagenesis.
• To determine the impact of RARgamma and RXRalpha inactivation on skin and hair follicle development and maintenance.

Summary:

• Null mutations in RARalpha or RXRbeta did not affect skin, while RARgamma deficiency altered the granular cell layer.
• Genetic inactivation of RXRalpha resulted in embryonic lethality, necessitating conditional mutagenesis for adult skin studies.
• Conditional inactivation of RXRalpha in adult mouse skin led to hair follicle degeneration and alopecia, suggesting RXRalpha/VDR heterodimer involvement in hair follicle homeostasis.
• Activation of RARgamma/RXR heterodimers by topical RA in suprabasal cells induced HB-EGF, stimulating basal cell proliferation.

Impact:

• Reveals the distinct and essential roles of RARgamma and RXRalpha in skin homeostasis and hair follicle development.
• Highlights the critical function of RXRalpha/VDR heterodimers in maintaining hair follicle integrity.
• Demonstrates the therapeutic potential of RA in stimulating skin cell proliferation through RARgamma/RXR signaling pathways.