The L1 immunoglobulin (Ig) subfamily of cell adhesion molecules includes L1, NrCAM, (Neuron glial-related cell adhesion molecule) and neurofascin. Their fundamental importance in mammalian development is highlighted by their constituting 1% of all membrane proteins in mature brains; their involvement in growth cone and synapse formation, and cancer development. Mutations can lead to human retardation and knockout studies show phenotypic changes. We have shown that these receptors bind to differing cytoplasmic proteins and so elicit differing signals. From these studies we found that both neurofascin and L1 but not NrCAM, can bind to the 4.1 superfamily protein member, Ezrin, but by different binding motifs (Gunn-Moore et al., 2006). Physiologically the interaction of Neurofascin and Ezrin appears to occur in the microvilli of interdigitating Schwann cells over the node of Ranvier, whilst L1 and Ezrin interaction is important for neuronal growth. This interaction between Neurofascin and Ezrin was via the FERM (4.1 Ezrin-Radixin-Moesin) domain of Ezrin and 28 amino acid sequence at the cytoplasmic C-terminus of Neurofascin. As part of these studies, we identified a novel FERM containing protein, “Willin”. Willin has a recognizable N-terminal FERM domain, which is able to bind both phospholipids and proteins (Gunn-Moore et al., 2005). Recently Willin has been identified as the human homologue to the Drosophila protein, Expanded, which associates with Merlin, a tumour suppressor protein responsible for neurofibromatosis. We have shown that Willin is expressed in the peripheral nervous system in Schwann cells and we are currently investigating its association with Neurofascin and Merlin.