Atg7 deficiency in Tmem119-Cre-targeted cells causes sustained neuroimmune dysregulation and disrupts early postnatal brain development

Abstract

Autophagy is a critical regulator of immune homeostasis, but the role of autophagy-related gene 7 (Atg7) in microglia during early postnatal brain development remains incompletely understood. Here, we investigated how Atg7 deficiency in Tmem119-Cre-targeted brain cells influences postnatal neuroimmune homeostasis and brain development. Conditional Atg7 knockout mice were generated by crossing Atg7 flox/flox mice with Tmem119-Cre mice. Postnatal growth, survival, brain histology, ultrastructure, and transcriptomic changes in sorted microglia-enriched CD45 + cells were evaluated using molecular, histological, and ultrastructural analyses. Atg7 deficiency in Tmem119-Cre-targeted cells was associated with severe postnatal growth retardation, disproportionate brain retention, hair loss and shortened survival. In the brain, Atg7 deficiency was associated with progressive disruption of microglial homeostasis features, characterized by reduced microglial abundance, simplified morphology, and decreased expression of homeostatic markers. Transcriptomic analysis further revealed persistent inflammatory reprogramming enriched for type I interferon signaling, innate immune responses, and antigen processing and presentation pathways. These findings were supported by increased cortical expression of interferon-responsive genes and pro-inflammatory cytokines. These neuroimmune alterations were associated with astrogliosis, altered oligodendrocyte-lineage development, and dysregulated myelination, indicating impaired postnatal brain maturation. Our findings indicate that Atg7 deficiency in Tmem119-Cre-targeted brain cells is associated with disrupted neuroimmune homeostasis, accompanied by alterations in cortical development and myelination. These results support an important role for Atg7 in maintaining neuroimmune homeostasis during early postnatal brain maturation.