Reelin, an extracellular glycoprotein, is involved in various of mammalian brain functions including neuronal migration, spine development and synaptic plasticity. Reelin binds to its cell surface receptors, and activates the downstream signaling through Src/Fyn kinases and adaptor protein Dab1.
Human genetic studies suggest that RELN is associated with schizophrenia and autism spectrum disorder. Previously, we reported that Orleans reeler (Reln^rl-Orl) mice showed behavioral alteration with deficits in sociability, motor coordination, and anxiety. However, the molecular mechanism underlying these phenotypes remains unknown.
We have screened molecules in the brains of Reln^rl-Orl mice which have an altered phosphorylation level compared to those in wild-type mice, and identified twinfilin1 (TWF1), an actin-monomer-binding protein, as a candidate protein. TWF1 plays an important role in the regulation of actin dynamics. Our studies have discovered that tyrosine phosphorylation level of TWF1 was decreased in Reln^rl-Orl mice. Besides, we also found that TWF1 was phosphorylated by Src mainly at the position of tyrosine 309. Therefore, we have hypothesized that tyrosine phosphorylation of TWF1 may be involved in the reelin-dependent processes for spine development and synaptic plasticity. To test this working hypothesis, we have generated a mouse model in the C57BL/6J strain with TWF1 gene mutation (TWF1-Y309F), and found that they exhibit abnormal spine morphology in prefrontal cortex of brain. Our results indicate that phosphorylation of TWF1 induced balanced dynamics of the neuronal cytoskeleton, which may be an important component of Reelin‘s function in spine development and synaptic plasticity.