Scientists at St. Jude Children’s Research Hospital have revealed that TEAD proteins—long viewed as key drivers of progenitor cell proliferation—also play a critical role in promoting differentiation when bound to an unexpected partner. Published May 19 in Genes & Development, the study overturns prevailing assumptions about neural development pathways and raises caution for drug strategies targeting TEAD in cancer therapy.
TEAD and YAP: Partners in Proliferation
The Hippo signaling pathway, in which TEAD and its canonical co-activator YAP operate, is renowned for regulating organ size by controlling cell growth and death. In the developing brain, YAP’s recruitment by TEAD to DNA activates genes that drive neural progenitor self-renewal and proliferation. YAP’s oncogenic potential has made it a focus in cancer research, but its “undruggable” nature has prompted pharmaceutical efforts to inhibit downstream effectors such as TEAD instead.
An Unexpected Phenotype: Progenitors Stalled in Immaturity
To probe TEAD’s functions in vivo, Xinwei Cao, PhD, and colleagues created conditional knockouts of all four TEAD family members (TEAD1–4) in the ventral telencephalon of mouse embryos. Contrary to expectations of reduced proliferation, progenitor cells lacking TEAD failed to exit the cell-cycle and differentiate. Instead, they accumulated in an immature state, producing insufficient numbers of neurons and glia for normal brain formation.
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“We anticipated fewer progenitors without TEAD-driven proliferation signals,” Cao explained, “but instead saw that cells were locked in a progenitor-like identity and could not mature.” This paradox led the team to search for alternative TEAD partners that might mediate differentiation.
INSM1 Emerges as a Context-Dependent Switch
Through co-immunoprecipitation and mass-spectrometry analyses of telencephalic tissue, the researchers detected robust interactions between TEAD proteins and INSM1, a zinc-finger transcription factor known for its role in neuroendocrine differentiation. Unlike YAP, which predominates in early progenitors, INSM1 levels rose as cells progressed toward differentiation.
Temporal Expression Dynamics Confirm Partner Swap
Using in situ hybridization and single-cell RNA sequencing, the team mapped YAP, TEAD and INSM1 expression across developmental time points. Early-stage progenitors expressed high YAP and TEAD, while INSM1 was virtually absent. By mid-neurogenesis, YAP transcripts declined sharply, and INSM1 expression surged in progenitor subsets destined for neuronal and glial lineages. This shift coincided with a biochemical switch: TEAD ceased binding YAP and instead associated with INSM1.
Functional Assays Demonstrate Differentiation Role
To test INSM1’s functional importance, the researchers knocked down INSM1 in isolated neural progenitor cultures. Even in the presence of TEAD, cells lacking INSM1 failed to upregulate differentiation markers (TUJ1 for neurons, GFAP for astrocytes), confirming that the TEAD–INSM1 complex is necessary for lineage commitment. Conversely, forced expression of INSM1 in early progenitors accelerated neuronal differentiation—but only when TEAD was present, indicating that the TEAD–INSM1 partnership is both necessary and sufficient to drive maturation.
Molecular Mechanisms: Redirecting TEAD’s Genomic Targets
Chromatin immunoprecipitation sequencing (ChIP-seq) revealed that TEAD–YAP complexes bind promoters of cell-cycle and proliferation genes (e.g., Cyclin D1, Myc), whereas TEAD–INSM1 complexes occupy enhancers of differentiation-associated loci (e.g., NeuroD1, Ascl1). Co-factor recruitment assays showed that TEAD–INSM1 recruits histone acetyltransferases (p300/CBP), opening chromatin at differentiation genes, while TEAD–YAP recruits the SWI/SNF complex to proliferation genes. This context-dependent switch in co-activator partners reprograms TEAD’s transcriptional output from mitogenic to differentiation programs.
Implications for Cancer Therapeutics and Neurodevelopmental Disorders
The discovery that TEAD proteins possess dual, context-specific roles carries significant implications for drug development. “Efforts to chemically inhibit TEAD in cancer could inadvertently impair critical differentiation processes in the brain or other tissues,” cautioned Cao. Small-molecule TEAD inhibitors now in preclinical trials may need reevaluation for off-target effects on progenitor differentiation, especially in pediatric patients.
Beyond oncology, the TEAD–INSM1 axis may illuminate mechanisms underlying neurodevelopmental disorders. Dysregulated timing of progenitor proliferation versus differentiation contributes to conditions such as microcephaly and macrocephaly. “Mutations affecting TEAD, INSM1 or associated co-factors could disturb the balance between progenitor expansion and neuronal production,” noted co-author Charles Perry. Future studies will investigate whether human genetic variants in this pathway correlate with intellectual disability or autism spectrum disorder.
Expert Commentary: A Paradigm Shift in Developmental Biology
Dr. Laura Martens, a neurodevelopmental biologist at Stanford University (unaffiliated with the study), praised the work as “a tour de force that revises our textbook model of TEAD function.” She added, “The notion that master transcription factors like TEAD can swap partners to reverse their regulatory logic is likely a general principle across organ systems.”
Next Steps: In Vivo Manipulations and Disease Models
Building on these findings, the St. Jude team plans to generate inducible TEAD–INSM1 interaction mutants to dissect temporal requirements for differentiation. They are also collaborating with clinical geneticists to screen patient cohorts for mutations in TEAD-binding domains of INSM1 or vice versa. Mouse models harboring such mutations may recapitulate human neurodevelopmental phenotypes, providing platforms for testing small-molecule modulators that selectively disrupt TEAD–YAP but spare TEAD–INSM1 interactions—or vice versa.
“We are only beginning to unravel the sophistication of transcriptional control in the developing brain,” said senior author Xinwei Cao. “Our study highlights the importance of context: a single protein can wear multiple hats depending on its partners. This versatility is both a marvel of biology and a cautionary tale for therapeutic targeting.”
Funding, Acknowledgments and Collaborations
The research, led by Cao’s laboratory in St. Jude’s Department of Developmental Neurobiology, received support from NIH grants R01NS119760 and P30CA021765, as well as ALSAC funding. First authors Charles Perry and Alfonso Lavado spearheaded molecular and genomic experiments. Contributing investigators included Venkata Thulabandu, Cody Ramirez, Joshua Paré, Rajiv Dixit, Jiyuan Yang, Jiyang Yu and Akhilesh Mishra (formerly of St. Jude).
By elucidating the dynamic partnerships of TEAD proteins, this work not only advances fundamental understanding of neurogenesis but also underscores the complexity underlying “druggable” targets. As researchers strive to translate molecular insights into therapies, the TEAD–INSM1 paradigm serves as a timely reminder: in biology, context is king.
