Proposed intracellular signaling involving Fer, p120ctn, SHP-2, β-catenin, and cadherin during synaptic development. Based on the results and current knowledge, we propose a signaling cascade (1–4) leading to synaptic formation (5 and 6). The model focuses on the role of Fer and cadherin components at the presynaptic compartment (left). (1) Fer is recruited by p120ctn to the cadherin complex. (2) Fer acts on SHP-2 tyrosine phosphatase to increase the phosphatase activity at the cadherin complex. This may be done in two ways that need to be characterized further: Fer may increase phosphorylation or modify the protein interaction of SHP-2, thereby increasing the phosphatase activity of SHP-2, or Fer enhances the recruitment of SHP-2 to the cadherin complex. (3) SHP-2 dephosphorylates β-catenin to strengthen the interaction between cadherin and β-catenin. (4) Cadherin adhesion and possibly other cell adhesion regulated by cadherin (e.g., nectin-mediated adhesion) are stabilized. Through this cadherin–catenin adhesion complex (5) in the presynaptic compartment, β-catenin acts as a scaffold using its PSD-95/disc large/ZO-1–binding domain to trap and stabilize the synaptic vesicles at the synaptic site. (5′) In the postsynaptic compartment, dendritic spine morphogenesis and recruitment of postsynaptic components are proceeded to form a mature and functional synapse (6). If this sequence is perturbed by deficiency of presynaptic Fer, we imagine the presynaptic vesicles will be scattered, and the disrupted integrity of cadherin–catenin will result in a failure in synapse formation and function (right).