The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway

作者：Hao Chen, Cole Ferguson, Dylan C. Mitchell, Isabel Risch, Amanda Titus, João A. Paulo, Andrew Hwang, L. P. Beck, Tsen‐Hsuan Lin, Wei Gu, Sheng‐Kwei Song, Carla M. Yuede, Hiroko Yano, Obi L. Griffith, Malachi Griffith, Steven P. Gygi, Azad Bonni, Albert H. Kim · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.115231 · 被引用次数：11 · 研究领域：Connective tissue disorders research、Ubiquitin and proteasome pathways、Epigenetics and DNA Methylation

Mutation or deletion of the deubiquitinase USP7 causes Hao-Fountain syndrome (HAFOUS), which is characterized by speech delay, intellectual disability, and aggressive behavior and highlights important unknown roles of USP7 in the nervous system. Here, we conditionally delete USP7 in glutamatergic neurons in the mouse forebrain, triggering disease-relevant phenotypes, including sensorimotor deficits, impaired cognition, and aggressive behavior. Although USP7 deletion induces p53-dependent neuronal apoptosis, most behavioral abnormalities in USP7 conditional knockout mice persist following p53 loss. Strikingly, USP7 deletion perturbs the synaptic proteome and dendritic spinogenesis independent of p53. Integrated proteomics and biochemical analyses identify the RNA splicing factor Ppil4 as a key substrate of USP7. Ppil4 knockdown phenocopies the effect of USP7 loss on dendritic spines. Accordingly, USP7 loss disrupts splicing of synaptic genes. These findings reveal that USP7-Ppil4 signaling regulates neuronal connectivity in the developing brain with implications for our understanding of HAFOUS pathogenesis and other neurodevelopmental disorders.