Cell-type-specific decoding of Hippo pathway inactivation drives seminiferous epithelial collapse and rete testis hyperplasia in the adult mouse testis

The Hippo pathway is a major regulator of epithelial homeostasis, but its role in the adult testis remains poorly defined. Here, we conditionally deleted Lats1 and Lats2 in WT1-expressing cells of the adult mouse testis, targeting both Sertoli cells and rete testis epithelial cells. Deletion of Lats1/2 caused rapid degeneration of the seminiferous epithelium, leading to near-complete germ cell loss, while simultaneously inducing marked hyperplasia of the rete testis. These tissue alterations were accompanied by vascular remodeling, macrophage accumulation, and extracellular matrix deposition. Cell-type-resolved transcriptomic analyses showed that Sertoli cells and rete testis epithelial cells have distinct baseline identities that shape their response to Hippo pathway inactivation. While both lineages activated shared YAP/TAZ-responsive genes, their broader outputs diverged sharply, with Sertoli cells preferentially activated structural remodeling programs, whereas rete testis epithelial cells robustly activated cell-cycle pathways and lost ciliogenesis-associated features. Regulatory network analysis further identified a conserved Hippo-responsive transcriptional backbone that was redeployed through lineage-specific regulons in each cell type. Together, these findings identify LATS1/2-mediated Hippo signaling as an essential regulator of adult testicular epithelial homeostasis and show that neighboring epithelial lineages decode Hippo pathway disruption through distinct transcriptional programs, resulting in divergent pathological outcomes.