Myrf ER-Bound Transcription Factors Drive C. elegans Synaptic Plasticity via Cleavage-Dependent Nuclear Translocation

Synaptic refinement is a critical step in nervous system maturation, requiring a carefully timed reorganization and refinement of neuronal connections. We have identified myrf-1 and myrf-2, two C. elegans homologs of Myrf family transcription factors, as key regulators of synaptic rewiring. MYRF-1 and its paralog MYRF-2 are functionally redundant specifically in synaptic rewiring. They co-exist in the same protein complex and act cooperatively to regulate synaptic rewiring. We find that the MYRF proteins localize to the ER membrane and that they are cleaved into active N-terminal fragments, which then translocate into the nucleus to drive synaptic rewiring. Overexpression of active forms of MYRF is sufficient to accelerate synaptic rewiring. MYRF-1 and MYRF-2 are the first genes identified to be indispensable for promoting synaptic rewiring in C. elegans. These findings reveal a molecular mechanism underlying synaptic rewiring and developmental circuit plasticity. [Display omitted] •C. elegans myrf-1 and myrf-2 are indispensable for developmental synaptic rewiring•MYRF proteins localize on ER and are cleaved into active N-terminal fragments•Nuclear translocation of N-terminal MYRFs drives synaptic rewiring•MYRF-1 and MYRF-2 function cooperatively in the same protein complex Synaptic rewiring of DD neurons in C. elegans provides a powerful in vivo model to study developmental plasticity of the nervous system. Meng et al. identified myrf-1 and myrf-2, members of the Myelin Regulatory Factor family of transcription factors, as essential regulators that drive synaptic rewiring via a cleavage-dependent mechanism.