Developmental Transcriptional Control of Mitochondrial Homeostasis is Required for Activity-Dependent Synaptic Connectivity

AbstractDuring neuronal circuit formation, local control of axonal organelles ensures proper synaptic connectivity. Whether this process is genetically encoded is unclear and if so, its developmental regulatory mechanisms remain to be identified. We hypothesized that developmental transcription factors regulate critical parameters of organelle homeostasis that contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Telomeric Zinc finger-Associated Protein (TZAP) as a temporal developmental regulator of neuronal mitochondrial homeostasis genes, includingPink1. InDrosophila, loss ofdTzapfunction during visual circuit development leads to loss of activity-dependent synaptic connectivity, that can be rescued byPink1expression. At the cellular level, loss ofdTzap/TZAPleads to defects in mitochondrial morphology, attenuated calcium uptake and reduced synaptic vesicle release in fly and mammalian neurons. Our findings highlight developmental transcriptional regulation of mitochondrial homeostasis as a key factor in activity-dependent synaptic connectivity.