Summary: New research from St. Jude Children’s Research Hospital reveals that TEAD proteins, previously known mainly for driving proliferation of neural progenitor cells, also play a decisive role in their maturation. TEADs promote proliferation when partnered with YAP early in development, but later associate with INSM1 to trigger differentiation into neurons and glia. This partner switch is essential for normal brain formation and has major implications for therapeutics that target the TEAD–YAP axis.
The discovery that TEAD proteins can switch partners—and therefore switch functions—clarifies how a single transcription factor family can both maintain progenitor pools and later promote cell maturation. It also highlights the need for nuanced strategies when considering TEAD-targeted treatments in cancer and other diseases.
Key Facts:
- Partner swap: TEAD proteins transition from associating with YAP (promoting proliferation) to binding INSM1 (promoting differentiation).
- Surprising knockout result: Removing TEAD proteins stalled neural progenitor progression, reducing neuron and glial production rather than increasing differentiation.
- Therapeutic caution: Strategies that block TEAD activity to counteract YAP-driven cancers may have unintended effects on brain development if context is ignored.
Source: St. Jude Children’s Research Hospital
Neural development relies on tightly regulated molecular interactions. The TEAD family of transcription factors has been associated with maintaining and expanding neural progenitor cells. However, St. Jude investigators demonstrate that TEADs perform a second, essential function: when paired with a different cofactor, they promote progenitor cells to differentiate into mature neural cell types.
Published recently in Genes and Development, the study clarifies how TEADs can perform seemingly opposite roles during ventral telencephalon development by changing their molecular partners at distinct lineage stages.
TEAD factors are well known to recruit YAP and TAZ to DNA to activate gene programs that drive tissue growth. YAP, in particular, is a potent growth effector and is often aberrantly active in cancers. In the developing brain, controlled YAP activity helps progenitors self-renew and proliferate to build the neural population.
While confirming YAP’s established role, the St. Jude team observed an unexpected effect when TEAD1 and TEAD2 were deleted in their mouse models. Instead of easing the transition to differentiation, TEAD loss caused progenitors in the ventral telencephalon to remain in an immature state and fail to generate sufficient neurons and glia.
“When TEAD proteins are absent, progenitor cells stall in an early state and do not progress to produce the neurons and glial cells required for a mature nervous system,” said Xinwei Cao, PhD, from the St. Jude Department of Developmental Neurobiology, the study’s corresponding author.
This counterintuitive result prompted the team to investigate whether TEADs play active roles beyond partnering with YAP to promote proliferation.
TEAD switches partners to drive differentiation
Further experiments uncovered a developmental partner switch: as progenitor cells advance along their lineage, YAP levels decline and INSM1, a transcriptional regulator known to influence neuronal differentiation, binds TEAD proteins. This interaction redirects TEAD activity from supporting self-renewal to promoting lineage progression and maturation into neurons and glia.
“We found that TEAD proteins change binding partners as progenitor cells move along their developmental trajectory,” Cao explained. “That shift enables TEAD to take on a fundamentally different function—helping progenitors mature rather than remain proliferative.”
Mechanistically, the study shows TEAD1/2 promote lineage progression in part by modulating Notch signaling and by cooperating with INSM1. These findings are consistent with conserved roles for TEAD–INSM complexes observed in other species and point to an evolutionarily preserved mechanism for regulating neural fate decisions.
The context-specific behavior of TEAD proteins carries immediate implications for drug development. Because YAP is challenging to target directly (“undruggable” in many contexts), pharmaceutical efforts have shifted toward inhibiting TEAD to block YAP-driven tumor growth. The St. Jude results caution that broad TEAD inhibition could interfere with normal neural differentiation and development, underscoring the importance of context-aware therapeutic design.
“Our work captures the complexity of neurodevelopment and emphasizes that intervention strategies must consider how molecular interactions change across cell states,” Cao said. “There is still much to learn about the core mechanisms that guide neural lineage progression.”
Authors and funding
The study’s first authors are Charles Perry and Alfonso Lavado of St. Jude. Coauthors include Venkata Thulabandu, Cody Ramirez, Joshua Paré, Rajiv Dixit, Jiyuan Yang, Jiyang Yu and Akhilesh Mishra. Funding was provided by the National Institutes of Health (grants R01NS119760 and P30CA021765) and ALSAC, the fundraising organization that supports St. Jude.
About this genetics and neurodevelopment research news
Author: Chelsea Bryant
Source: St. Jude Children’s Research Hospital
Contact: Chelsea Bryant – St. Jude Children’s Research Hospital
Image: Image credit: Neuroscience News
Original Research: Closed access. “TEAD switches interacting partners along neural progenitor lineage progression to execute distinct functions” by Xinwei Cao et al., Genes and Development.
Abstract
TEAD switches interacting partners along neural progenitor lineage progression to execute distinct functions
TEAD transcription factors are central to the Hippo pathway as DNA-binding factors that recruit coactivators YAP and TAZ. Despite the pathway’s importance, in vivo roles for TEAD in mammalian neural development have been incompletely defined. Comparing mouse models lacking TEAD1/2 to those deficient in YAP/TAZ, the authors show TEAD1/2 perform both YAP/TAZ-dependent and -independent functions during ventral telencephalon formation. Loss of TEAD1/2 and loss of YAP/TAZ both disrupt neuroepithelial apical junctions, but they have opposite effects on progenitor lineage progression: YAP/TAZ loss depletes early progenitors and increases later progenitors, while TEAD1/2 loss expands early progenitors and reduces later progenitors. The study demonstrates TEAD1/2 promote lineage progression at least in part by inhibiting Notch signaling and by cooperating with INSM1, revealing an evolutionarily conserved transcriptional mechanism for neural fate regulation.