TEAD Proteins Switch Partners to Drive Neural Cell Maturation

The basic mechanisms that govern neural development are complex, and, as research from St. Jude Children’s Research Hospital suggests, the underlying processes can sometimes appear contradictory. The TEAD protein family is believed to promote the proliferation and self-renewal of progenitor cells in the brain.

According to research from St. Jude, when these same proteins bind to different partners, they can also promote differentiation. This finding sheds light on the complex processes underlying neural development and highlights potential risks in developing therapies that specifically target TEAD proteins. The study was published in the journal Genes and Development.

TEAD proteins are known for their ability to recruit YAP to DNA, a protein that activates genes involved in tissue growth. YAP is a well-established oncogene, often aberrantly activated in various cancers, where it drives excessive cell replication.

During normal brain development, YAP is tightly regulated and promotes the self-renewal and proliferation of neural progenitor cells. While the St. Jude team confirmed this role of YAP in their research, they also made an unexpected discovery: knocking out TEAD proteins in their laboratory models produced results that were contrary to expectations.

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.

Xinwei Cao, Ph.D., Study Corresponding Author, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital

This finding raised an intriguing question: If TEAD proteins are YAP’s partners in promoting cell proliferation, how could the absence of TEAD lead to a halt in cell differentiation? Cao and her team set out to investigate this phenomenon.

TEAD Proteins Change Partners to Promote Differentiation

They discovered that INSM1 is the “secret” partner of TEAD proteins. As neural progenitor cells progress through development and YAP levels decline, INSM1 steps in to bind TEAD proteins. This new partnership causes TEAD to shift its role, promoting cell differentiation instead of self-renewal.

We found that TEAD proteins switch interacting partners as neural progenitor cells move along their developmental path. This change allows TEAD to play a completely different role, helping progenitor cells mature and produce neurons and glia.

Xinwei Cao, Ph.D., Study Corresponding Author, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital

Drug development is significantly affected by the context-specific functions of TEAD proteins. Although YAP is considered “undruggable,” it has been explored as a potential oncogene target. As a result, some companies have attempted to target TEAD in order to block the downstream effects of YAP. However, this study shows that inhibiting TEAD may lead to unintended consequences.

We have 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. It also reminds us that there is still much left to uncover about the fundamental mechanisms driving neurodevelopment.

Xinwei Cao, PhD, Study Corresponding Author, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital