Corresponding author Xinwei Cao, PhD, St. Jude Department of Developmental Neurobiology.
The fundamental processes that govern neural development are complex and, as findings by scientists at St. Jude Children’s Research Hospital demonstrate, the underlying driving forces can even appear conflicting. The TEAD family of proteins is thought to promote self-renewal and proliferation of progenitor cells in the brain. However, St. Jude researchers have discovered that these same proteins can also play a role in differentiation when they have a different binding partner. This discovery sheds light on the intricate mechanisms of neural development and highlights potential pitfalls for developing therapies that target TEAD proteins. The study was published yesterday in Genes and Development.
TEAD proteins are well known to recruit YAP to DNA, a protein that activates genes involved in tissue growth. YAP is an infamous oncogene; it is aberrantly activated in many cancers and drives excessive cell replication. During normal brain development, YAP is tightly controlled and drives neural progenitor cells to self-renew and proliferate. While the St. Jude group confirmed this function of YAP with their studies, they also made a surprising discovery: Removing or “knocking out” TEAD proteins in their lab models had an effect opposite to what was expected.
“Without TEAD proteins, neural progenitor cells in a specific region of the brain, the ventral telencephalon, became stuck in their immature state and failed to produce enough neurons and glia, the building blocks of a mature nervous system,” said corresponding author Xinwei Cao, PhD, St. Jude Department of Developmental Neurobiology.
This finding raised an intriguing question: If TEAD proteins are YAP’s partners in promoting cell proliferation, how could removing TEAD cause cells to stall instead of differentiating? Cao and her team set out to understand how this could be the case.
TEAD proteins change partners to promote differentiation
The group found that TEAD proteins have a “secret” partner called INSM1. As neural progenitor cells progress through their developmental journey, YAP levels decrease, and INSM1 steps in to bind TEAD proteins. This new partnership causes TEAD to switch gears, promoting cell differentiation instead of self-renewal.
“We found that TEAD proteins switch interacting partners as neural progenitor cells move along their developmental path,” Cao said. “This change allows TEAD to play a completely different role, helping progenitor cells mature and produce neurons and glia.”
The context-specific roles of TEAD proteins carry important implications for drug development. As an oncogene, scientists have investigated YAP as a target, but it is considered “undruggable.” Companies seeking to block the downstream effects of the undruggable YAP proteins have therefore sought to drug TEAD instead. This study, however, shows that inhibiting TEAD could have unexpected consequences.
“We’ve captured the complexity of brain development, demonstrating how important it is to account for context as we study and look for ways to disrupt these processes,” Cao said. “It also reminds us that there’s still much left to uncover about the fundamental mechanisms driving neurodevelopment.”
Authors and funding
The study’s first authors are Charles Perry and Alfonso Lavado of St. Jude. The other authors are Venkata Thulabandu, Cody Ramirez, Joshua Paré, Rajiv Dixit, Jiyuan Yang and Jiyang Yu of St. Jude, and Akhilesh Mishra, formerly of St. Jude.
The study was supported by grants from the National Institutes of Health (R01NS119760 and P30CA021765) and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.