Brain development and neurogenesis underlying brain evolution and mental illness
Mechanisms of brain regionalization/neuronal differentiation and migration
The brain, a highly complex structure, originates from an ectodermal sheet-like structure called the neural plate. In the early brain, region-specific genes are expressed to correctly regionalize the brain. Since the transcriptional regulator Pax6 is expressed in various regions during brain processes, we have analyzed spontaneous Pax6 mutant mice and rats and applied whole embryo culture methods for gene transfer (Fig. 1, Takahashi et al., 2002; Kikkawa et al., 2017) that Pax6 influences brain patterning, neuronal differentiation and migration, and neuronal circuitry formation (see our review, Osumi et al., 2008). Pax6 is expressed in neural stem cells and is an important molecule that regulates both proliferation and differentiation of neural stem cells (see our review, Kikkawa et al., 2019).
Fig. 1: Taken from Takahashi et al., 2002; Takahashi and Osumi, 2010; Kikkawa et al., 2017, Kikkawa et al., 2019
We have previously found that the cell cycle regulator, Cyclin D2, is localized at the tip of the basement membrane surface outside the brain primordium and is responsible for maintaining the cell fate in an undifferentiated state (Tsunekawa et al., 2012). Currently, we are approaching the mRNA transport mechanism of Cyclin D2 using the genome editing by CRIPR/Cas9 technology (Fig. 2).
Fig. 2: Genome editing by CRIPR/Cas9 technology
Neural development and neurodevelopmental disorders
Autism spectrum disorder (ASD), mental retardation, and attention deficit hyperactivity disorder are called "neurodevelopmental disorders" and are known to be caused by impairment of some developmental processes of the brain. In addition to the declining birthrate, the incidence of neurodevelopmental disorders is currently reported to be increased (e.g., 1 in 50-60 people in the case of ASD), raising concerns about a significant decrease in the number of future workers.
The transcriptional regulator Pax6 is a commander molecule that regulates expression of various genes in order for various cellular phenomena to occur. During fetal cortical development, we found that many of the downstream genes regulated by Pax6 include autism-related genes, suggesting that Pax6 may be one of the genes responsible for developmental disorders (Figure 3, Kikkawa et al., 2019).
Fig. 3: Taken from Kikkawa et al., 2019
Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder with a relatively high incidence of mental retardation and autism-like symptoms. FXS has been shown to be caused by an abnormality in the FMR1 gene, and its product, FMRP protein, post-transcriptionally regulates its target mRNAs. We have comprehensively identified target molecules of FMRP in the fetal mouse brain and found that the mTOR pathway, a key that regulates protein synthesis in the fetal brain, is abnormally activated in mice lacking Fmr1 gene (Fig. 4, Casingal et al., 2020). This study is expected to contribute to the development of research on hereditary developmental disorders in the developing brain.
Fig. 4: Taken from Casingal et al., 2020
