New Insights into the Hippo Pathway: TEAD1 Essential for Myelination and Nerve Repair

The Hippo pathway appears crucial for both the initial myelination of axons and their remyelination following injury, making it a potential target for therapeutic interventions in neuropathies. At the 2024 Peripheral Nerve Society (PNS) annual meeting in Montreal, Canada, Steven Scherer, Professor of Neurology at the University of Pennsylvania, presented the 2024 eLife article by Matthew Grove et al. Titled "TEAD1 is Crucial for Developmental Myelination, Remak Bundles, and Functional Regeneration of Peripheral Nerves," this study offers novel insights into the Hippo pathway's involvement in Schwann cell function and neuropathy. Dr. Scherer highlighted the importance of this research, stating, "There is a science of neuropathy that is not always evident, and this is a pathway that we have not heard much about."

The Hippo pathway involves co-transcription factors Yap and TAZ binding to the transcription factor TEAD, leading to gene activation. This pathway is essential for Schwann cell function and myelination and is activated by laminar receptors. In mice with a double knockout of Yap and TAZ, researchers observed clusters of unmyelinated axons, demonstrating the essential role of the Yap-TAZ pathway in myelination. Single knockouts produced less severe defects, indicating that both factors are necessary for proper Schwann cell function. Deleting Yap and TAZ genes in mature Schwann cells, rather than during early development, did not prevent initial myelination but hindered remyelination after nerve injury. This finding suggests that the Yap-TAZ pathway is crucial for both Schwann cell development and their ability to repair and regenerate nerve fibers after injury.

Further investigations revealed that the TEAD gene, particularly TEAD1, is highly expressed in both myelinating and non-myelinating Schwann cells. Researchers created a conditional knockout of TEAD1, which led to similar myelination defects as seen in the Yap-TAZ knockout, supporting the role of this pathway in Schwann cell function. These findings underscore the importance of the Hippo pathway in Schwann cell development and nerve regeneration. Previous studies showed that the Hippo pathway transcriptional effectors, Yap and TAZ, are essential for Schwann cells to develop, maintain, and regenerate myelin. Although TEAD1 has been implicated as a partner transcription factor, the mechanisms by which it mediates Yap/TAZ regulation of Schwann cell myelination were unclear. This study demonstrates that TEAD1 is crucial for Schwann cells to develop and regenerate myelin. Additionally, TEAD1 is essential for non-myelinating Schwann cells to enwrap nociceptive axons in Remak bundles.

Understanding the role of the Hippo pathway in Schwann cell development and nerve regeneration can potentially lead to significant advances in treating demyelinating diseases and nerve injuries.