Involvement Of Dysbindin-1, A Schizophrenia Related Protein, In Neuronal Development

Schizophrenia is a severe mental disorder that affects 0.5%-1% of the population and has a strong hereditary component. To date, many susceptibility genes have been found to be associated with schizophrenia by genetic studies. Genetic variations in the DTNBP1 gene encoding dysbindin-1 have been linked to schizophrenia in multiple populations. Some of these genetic variations are associated with a decreased level of dysbindin-1 mRNA in the prefrontal cortex of schizophrenia patients. In the hippocampus of schizophrenia patients, the protein levels of dysbindin-1 are significantly reduced. Functional studies have revealed that genetic variations of DTNBP1 modulate prefrontal brain function. These studies have shown a strong connection between dysbindin-1 function and the pathogenesis of schizophrenia.Previous studies have shown that dysbindin-1 functions both pre- and post-synaptically through interaction with partners to regulate neurotransmitter release and signal transduction. Therefore, lose of fuctions of dysbindin-1 in brain is associated with pathogenesis of schizophrenia by alteration neurotransmitter system.Recently, dysbindin-1 has also been documented to be involved in neuronal development. However, the mechanisms are still largely unknown. Neuronal development is also thought to involve into pathogenesis of schizophrenia, thus investigation of the involvement of neuronal development by dysbindin-1 will help us to know schizophrenia much better.In this study, we identified necdin as a binding partner of dysbindin-1 from human fetal cDNA library using a yeast two-hybrid screen. We demonstrated that dysbindin-1 could regulate transcriptional activity of p53 by altering the cellular distribution of necdin, and further influencing the neuron development through promoting p53 transcriptional activity. Our main results include:1,We firstly identified necdin as a novel binding partner of dysbindin-1 from human fetal cDNA library using a yeast two-hybrid screen. In vitro pull-down assay and immunoprecipitation assay further demonstrated their interaction and confirmed that 97-118 amino acids of dysbindin-1 is required for its interaction with necdin. Meanwhile, Immunocytochemistry and report gene assay showed that dysbindin-1 translocated necdin from nucleus to cytoplasm by interacting with necdin. Further, dysbindin-1 promoted the transcriptional activity of p53 by attenuating the nuclear distribution of necdin.2,Our results further showed the connection between dysbindin-1 and neuronal development due to transcriptional activity of p53 is critical for neuron development. Knockdown of dysbindin-1 caused the neurite outgrowth defect in culture cell lines. The expressions of p53 target genes Coronin 1b and Rab13 that is required during neuronal development also decreased along with the reduction of dysbindin-1. Moreover, overexpression of p53 restores the neurite outgrowth blocked by dysbindin-1 knockdown. These data suggested dysbindin-1 influenced the neuronal development through p53 pathway.3,In brains of dysbindin-1 null mice (the sandy strain), p21, Coronin 1b and Rab13 levels are reduced. Furthermore, primary cultured cortical neurons from sandy mice display neurite outgrowth defects when compared with those from wild-type mice. These results further suggested dysbidin-1 involved into neuronal development by influencing p53 transcriptional activity in vivo.Thus, our data showed that dysbindin-1 promote p53's transcriptional activity by altering cellular distribution of necdin and provided a potential mechanism to explain the role of dysbidin-1 plays in neurite outgrowth.