The vast majority of excitatory synapses are made on the heads of dendritic spines, highly dynamic structures. The shape of a neuron’s dendritic arbour determines the set of axons with which it may form synaptic contacts, thus establishing connectivity within neural circuits. Dynamic cytoskeleton remodelling is an essential step during this process. The actin filaments are believed to be the basic structural foundation that are responsible for their shape. Membrane protein may act through an intracellular signalling pathways, which ultimately converge on the cytoskeleton. However, the molecular mechanisms involved in these steps are not well understood. Here, we show that the integral membrane protein Plasticity-related gene-5 (PRG-5), a member of the vertebrate- and brain-specific PRG family, is involved in dendritic spine formation. Mutagenesis experiments in PRG-5 identify the single amino acids that are important for this induction.