Schizophrenia-associated Mitotic Arrest Deficient-1 (MAD1) regulates the polarity of migrating neurons in the developing neocortex

Abstract

Although large-scale genome-wide association studies (GWAS) have identified an association between MAD1L1 (Mitotic Arrest Deficient-1 Like 1) and the pathology of schizophrenia, the molecular mechanisms underlying this association remain unclear. In the present study, we aimed to address these mechanisms by examining the role of MAD1 (the gene product of MAD1L1) in key neurodevelopmental processes in mice and human organoids. Our findings indicated that MAD1 is highly expressed during active cortical development and that MAD1 deficiency leads to impairments in neuronal migration and neurite outgrowth. We also observed that MAD1 is localized to the Golgi apparatus and regulates vesicular trafficking from the Golgi apparatus to the plasma membrane, which is required for the growth and polarity of migrating neurons. In this process, MAD1 physically interacts and collaborates with the kinesin-like protein KIFC3 (kinesin family member C3) to regulate the morphology of the Golgi apparatus and neuronal polarity, thereby ensuring proper neuronal migration and differentiation. Consequently, our findings indicate that MAD1 is an essential regulator of neuronal development and that alterations in MAD1 may underlie schizophrenia pathobiology.

Glia Cells Control Olfactory Neurogenesis by Fine-Tuning CXCL12

“…Another important aspect revealed by transcriptome analysis is that half (27 of 55) of the downregulated genes in GBCs of Mpz-Cre;Ackr3 LoxP/LoxP mice are known to be involved in neurogenesis (marked red in Figure 4A). For example, downregulated Mad1l1 (mitotic arrest deficient 1 like 1) contributes to morphogenesis during brain development by regulating the integrity of the Golgi complex [60]. Interestingly, we detected an altered morphology of the Golgi apparatus in olfactory neurons of mice with deficient CXCL12 scavenging.…”

Calneuron 1 reveals the pivotal roles in schizophrenia via perturbing human forebrain development and causing hallucination-like behavior in mice

“…Schizophrenia is considered as to be polygenic psychiatric disorder 34,35 and previous studies have reported that some risk genes disrupt human developing neuronal and glial cells in schizophrenia, such as PCDHA 12 , C4A 36,37 , NRXN1 18 , DISC1 38 and MAD1 39 . There are 106 protein-coding risk genes identified by fine-mapping and functional genomic analysis based on the largest GWAS of schizophrenia so far 6 .…”

Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration

“…In NEO vs. normal, we validated seven genes (AGTPBP1, BBS5, CERKL, FGFBP2, KIFC3, RORα, and ZNF292) from our DEGs, DSGs, and in an independent bulk-RNAseq dataset (Table 7). Independently, these genes have been linked to AMD (RORα [30,55]), eye disease (BBS5 [82], CERKL [83][84][85], KIFC3 [86,87]) and other immune/neurodegenerative condi-tions (AGTPBP1 [88], FGFBP2 [89,90], KIFC3 [91,92], ZNF292 [93]). As previously reported, RORα has also been shown to interact with the AMRS2/HTRA1 locus [30,55].…”