Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi via Paracrine...

Area of Science:

• Developmental Biology
• Dermatology
• Genetics

Background:

• Giant congenital nevi can lead to serious complications like melanoma.
• The genetic and molecular underpinnings of nevus development remain largely unknown.
• The sonic hedgehog (Shh) pathway regulator Cdon was previously implicated in nevus formation.

Purpose of the Study:

• To validate Cdon as a nevus modifier gene.
• To elucidate the mechanism by which Shh signaling influences nevogenesis.
• To explore therapeutic strategies for giant congenital nevi.

Main Methods:

• Studied Cdon knockout mice to assess nevus development.
• Utilized a mouse model with melanocyte NRAS^Q61K and varying keratinocyte Shh pathway activity.
• Measured Shh pathway activity using Gli1 and Gli2 expression.
• Investigated Shh pathway activity in human congenital nevi.
• Administered Shh and endothelin antagonists to suppress nevus development.

Main Results:

• Cdon knockout mice developed blue nevi independently of somatic melanocyte mutations.
• Increased keratinocyte Shh pathway activity correlated with giant congenital nevus formation in NRAS^Q61K mice.
• Shh pathway components were active near human congenital nevi.
• Shh signaling exacerbates nevogenesis by inducing endothelin-1 release from keratinocytes.
• Shh and endothelin antagonists reduced nevus development in mice.

Conclusions:

• Keratinocyte-derived cytokines, such as endothelin-1, play a role in exacerbating nevogenesis.
• Targeting the Shh pathway and endothelin-1 offers potential therapeutic avenues for giant congenital nevi.
• Germline genetic variations, alongside somatic mutations, significantly impact melanocytic nevus characteristics.