UNC-4/UNC-37-dependent repression of motor neuron-specific genes controls synaptic choice in Caenorhabditis elegans

The UNC-4 homeoprotein and the Groucho-like corepressor UNC-37 specify syna ptic choice in the Caenorhabditis elegans motor neuron circuit. In unc-4 mu tants, VA motor neurons are miswired with inputs from interneurons normally reserved for their lineal sisters, the VB motor neurons. Here we show that UNC-4 and UNC-37 function together in VA motor neurons to repress VB-speci fic genes and that this activity depends on physical contact between UNC-37 and a conserved Engrailed-like repressor domain (ehl) in UNC-4. Missense m utations in the UNC-4 ehl domain disrupt interactions between UNC-4 and UNC -37 and result in the loss of UNC-4-dependent repressor activity in vivo. A compensatory amino acid substitution in UNC-37 suppresses specific unc-4 a lleles by restoring physical interactions with UNC-4 as well as UNC-4-depen dent repression of VB-specific genes. We propose that repression of VB-spec ific genes by UNC-4 and UNC-37 is necessary for the creation of wild-type i nputs to VA motor neurons. The existence of mammalian homologs of UNC-4 and UNC-37 indicates that a similar mechanism could regulate synaptic choice i n the vertebrate spinal cord.