Studies on the role of novel schizophrenia-associated gene, MAD1L1 (Mitotic Arrest Deficient-1 Like 1) in the neuronal development

Abstract

Schizophrenia (SZ) is a major mental disorder showing cognitive and behavioral defects. Environmental and genetic backgrounds cause SZ. As a neurodevelopmental disorder, SZ patients show distinct brain structures such as reduced cortical volume and larger ventricle size. Until now, researchers have struggled to find novel SZ risk genes from human GWAS (Genome-Wide Association Studies). Many novel candidates of schizophrenia risk genes were characterized, but mechanistic insights remain elusive. MAD1L1 (Mitotic Arrest Deficient-1 Like 1) is one of the top-ranked candidates of SZ risk genes. Multiple GWAS and epigenetics studies suggest a strong association of MAD1L1 with SZ predisposition. MAD1 (a gene product of MAD1L1) is a SAC (Spindle Assembly Checkpoint) regulator during mitosis and is also involved in chromosome segregation. Also, cytoplasmic MAD1 is localized to the Golgi apparatus and regulates cell adhesion and migration. However, its functional and molecular mechanisms relevant to schizophrenia pathophysiology have not been fully explored yet. Here, I found that MAD1L1 is highly expressed in the developing brain and conducts distinct functions in neurons. MAD1 is localized to the Golgi apparatus and regulates the determination of neuronal polarity, which is crucial for regulating neuronal migration and neurite differentiation. Indeed, MAD1 deficient neurons showed altered neuronal polarity, resulting in abnormal migration and neurite outgrowth. Also, MAD1 deficient cells showed changes in Golgi morphology and functionality. I identified kinesin family protein KIFC3 as one of the novel interaction partners of MAD1. MAD1 is crucial for recruiting KIFC3 to the Golgi apparatus. Furthermore, I discovered that interaction between MAD1 and KIFC3 is essential for Golgi integrity and functionality, further determining the neuronal polarity. Taken together, these data reveal that MAD1L1 is an important regulator of neuronal development, which can also be linked to schizophrenia pathology.