Since DISC1 (disrupted in schizophrenia 1) has been identified as a risk gene factor of psychiatric disease from a large Scottish family, tons of thousands of studies concentrate on this mystery gene. Mutations of DISC1 have been associated with major psychiatric disorders including schizophrenia, bipolar disorder and major recurrent depression. Despite the hundreds of DISC1 binding proteins and various aspects of functions are reported, little is known about how DISC1 interacts with other proteins structurally to impact human brain development.

In the first half of this thesis, we focus on the regulation of mitosis and neurogenesis via DISC1/Ndel1 interaction. First, we confirmed the strong direct interaction between DISC1 C-terminal tail and Ndel1 C-terminal coiled-coil regio...[ Read more ]

Since DISC1 (disrupted in schizophrenia 1) has been identified as a risk gene factor of psychiatric disease from a large Scottish family, tons of thousands of studies concentrate on this mystery gene. Mutations of DISC1 have been associated with major psychiatric disorders including schizophrenia, bipolar disorder and major recurrent depression. Despite the hundreds of DISC1 binding proteins and various aspects of functions are reported, little is known about how DISC1 interacts with other proteins structurally to impact human brain development.

In the first half of this thesis, we focus on the regulation of mitosis and neurogenesis via DISC1/Ndel1 interaction. First, we confirmed the strong direct interaction between DISC1 C-terminal tail and Ndel1 C-terminal coiled-coil region using ITC, FPLC and other biochemical approaches. Then we solved the high resolution structure of DISC1 C-terminal tail in complex with its binding domain of Ndel1 with the help of NMR spectrometry. Surprisingly, we found that DISC1 C-terminal peptide can significantly elongate the mitosis time length and interfere with cell cycle progression. Mechanistically, DISC1 regulates Ndel1’s kinetochore localization but not its centrosome localization during mitosis. Further study uncovers DISC1 can regulate the interaction between Ndel1 and CENPF, one of major outer kinetochore protein. Our study uncovers a new possible mechanism of DISC1-mediated mitosis and neurogenesis regulation and has implications for how risk gene factors may contribute to psychiatric disorders.

In the second half of this thesis, we focus on the regulation of gene transcription via DISC1/ATF4 interaction. Similar to the DISC1/Ndel1 project, we also confirmed the strong direct interaction between DISC1 C-terminal tail and ATF4 C-terminal helix region using similar biochemical approaches. Then we solved the high resolution structure of ATF4 C-terminal coiled-coil in complex with DISC1 C-terminal tail. Moreover, we showed that DISC1 can totally disrupt the dimerization of ATF4 which is also mediated by DISC1 binding site. Consistently, we use ITC and NMR spectra method to clearly demonstrate DISC1 can release ATF4 from DNA via strong interaction with ATF4 and disruption the dimerization of ATF4. Our study uncovers another possible mechanism of DISC1-mediated transcriptional regulation.