The Hippo pathway: Horizons for innovative treatments of peripheral nerve diseases

Abstract

Initially identified in Drosophila, the Hippo signaling pathway regulates how cells respond to their environment by controlling proliferation, migration and differentiation. Many recent studies have focused on characterizing Hippo pathway function and regulation in mammalian cells. Here, we present a brief overview of the major components of the Hippo pathway, as well as their regulation and function. We comprehensively review the studies that have contributed to our understanding of the Hippo pathway in the function of the peripheral nervous system and in peripheral nerve diseases. Finally, we discuss innovative approaches that aim to modulate Hippo pathway components in diseases of the peripheral nervous system.

Keywords: Hippo; YAP/TAZ; nerve injury and regeneration; neurofibromatosis; peripheral neuropathy; schwann cell.

FIGURE 1

Core components of the Hippo pathway. The Hippo pathway control the cytoplasmic-nuclear shuttling of YAP/TAZ. A, When the Hippo pathway is active (ON), LATS1/LATS2 kinases phosphorylate YAP/TAZ, causing either their cytoplasmic retention or degradation. NF2 contributes to the Hippo pathway activation. B, When the Hippo pathway if inactive (OFF), YAP and TAZ are not phosphorylated and shuttle into the nucleus to regulate gene expression. Mechanical stimuli and Actin dynamics can regulate LATS1/LATS2 kinases

FIGURE 2

Non-comprehensive, schematic representation of peripheral nerve development (green background) and pathology (blue background). The PNS is formed from the soma and axons of sensory and autonomic neurons, and from the axons of motor neurons. These axons are ensheathed by glial cells and surrounded by blood vessels, endoneurial fibroblasts, perineurial and epineurial cells. Many of these cell types derive from the neural crest. Schwann cells are the major type of ensheathing glia. Yet, the PNS also includes region-specific ensheathing glia: PNS ganglia are associated with satellite cells and axons at the sensory terminals are surrounded by nociceptive glial cells. Magenta notes indicate the steps where an involvement of the Hippo pathway or YAP/TAZ have been described. Ax, axon; BL, basal lamina; CM, compact myelin

FIGURE 3

Schematic representing the different approaches to pharmacologically target the Hippo pathway. Group I drugs enhance phosphorylation of YAP/TAZ. Group II drugs directly modify the YAP/TAZ-TEAD interaction. Group III drugs target the genes regulated by YAP/TAZ-TEAD