Lef1 is dispensable for blood-brain barrier integrity despite its dominant role in endothelial Wnt signaling

The blood-brain barrier (BBB) is a specialized vascular structure essential for CNS homeostasis, whose formation and maintenance are governed by the canonical Wnt signaling pathway. While the upstream ligands and receptors are well-characterized, the downstream transcriptional architecture remains poorly understood. Here, we investigate the functional requirement for Lef1, the most abundant Tcf/Lef transcription factor and a hallmark readout of Wnt activity in brain endothelial cells (BECs). Utilizing a conditional, endothelial-specific deletion strategy in mice, we demonstrate that loss of Lef1 during either embryonic development or adult homeostasis significantly dampens Wnt transcriptional output. Surprisingly, high-resolution molecular and functional analysis reveals that this reduction results in only minor dysregulation of the BBB-specific gene program and is insufficient to trigger barrier breakdown. Our results establish that Lef1 is not an obligatory effector of the Wnt-dependent BBB maintenance program. These findings suggest a resilient transcriptional framework where redundant Tcf/Lef family members or alternative regulatory circuits preserve CNS microvasculature function, providing new insights into the genetic robustness of the blood-brain barrier. Research Highlights Lef1 is the predominant Tcf/Lef transcription factor in the brain endothelium and a hallmark of vascular Wnt signaling. Endothelial-specific Lef1 deletion significantly attenuates Wnt transcriptional output during both CNS vascular development and adult homeostasis. Loss of Lef1 causes only minor perturbations in the BBB-specific gene program, rather than a global loss of endothelial identity. Structural and functional BBB integrity is preserved in the absence of Lef1, revealing a high degree of vascular resilience. The findings demonstrate that Lef1 is not an obligatory effector for the maintenance of the specialized CNS microvasculature.