Genipin Crosslinks the Extracellular Matrix to Rescue Developmental and Degenerative Defects, and Accelerates...

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Peripheral nervous system (PNS) disorders, including neuropathies from diabetes and chemotherapy, affect a large population.
• Familial Dysautonomia (FD), a genetic disorder impacting the PNS due to an *ELP1* mutation, serves as a model for studying PNS dysfunction.
• Current understanding of human PNS development is limited, with no effective treatments for related disorders.

Approach:

• A chemical screen using human pluripotent stem cells (hPSCs) identified compounds to improve sensory neuron (SN) differentiation in FD.
• Genipin was identified as a compound that restores neural crest and SN development in both hPSC and mouse models of FD.
• Mechanistic studies revealed genipin's effects on extracellular matrix (ECM) crosslinking, stiffness, actin cytoskeleton, and YAP-dependent gene transcription.

Key Points:

• Genipin treatment rescued SN differentiation and prevented neuronal degeneration in FD models.
• The compound enhances axon regeneration in sensory, sympathetic, and cortical neurons *in vitro*.
• Genipin's mechanism involves modulating ECM properties and the actin cytoskeleton, influencing YAP signaling.

Conclusions:

• Genipin shows promise as a therapeutic agent for neurodevelopmental and neurodegenerative diseases affecting the PNS.
• The findings suggest genipin's potential for treating conditions like peripheral neuropathies and enhancing neuronal repair.
• Genipin represents a potential drug candidate for improving outcomes in patients with PNS disorders and CNS injuries.