National Center of Neurology and PsychiatryNational Institute of NeuroscienceDepartment of Biochemistry & Cellular Biology

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Research Overview

Understanding how the brain is formed leads to understanding how we acquire intelligence and how its function can be disrupted, leading to disease. However, many mysteries remain regarding the detailed mechanisms by which the brain, with its complex and elaborate structure and function, is constructed and maintained.

To answer these questions, we conduct research aimed at elucidating the molecular and cell biological basis of brain development, focusing primarily on the cerebellum.

The brain contains a diverse variety of neurons, each present in the appropriate number, forming the foundation that supports normal brain function. However, the mechanisms by which "(A) diverse types of neurons and glial cells are differentially generated from limited genetic information" and "(B) the appropriate number of each type of neuron and glial cell is generated at the appropriate timing" remain largely unknown. We have been addressing these important neuroscientific questions using the mouse cerebellum as a model system. Regarding (A), we have reported the elucidation of the functions of key transcription factors (PTF1A, ATOH1) that differentially generate inhibitory and excitatory neurons (Neuron 2005, J. Neurosci 2007, Development 2009, J. Neurosci 2014, Cell Rep 2018), and the mechanism by which transcription factors (OLIG2, GSX1) differentially generate Purkinje cells and interneurons (both inhibitory neurons) (Nature Communications 2014). Regarding "(B) the mechanism for generating the appropriate number of each neuronal type at the appropriate timing," we have begun to clarify part of the mechanism using cerebellar granule cell progenitors (GCPs) and their differentiation into granule cells (GCs) as a model system (J. Neurosci 2018, EMBO J 2021, eNeuro 2021).

We will continue to conduct research to answer the questions (A) and (B) outlined above. Below we describe some of what we have learned so far and the research we are currently conducting.

1. Elucidating the function of transcription factor MEIS1 in cerebellar development

Myeloid ecotropic viral integration site 1 (MEIS1) is a homeodomain transcription factor known to be expressed in various tissues and some tumors from development through adulthood. MEIS1 shows strong expression in the central nervous system, particularly in the cerebellar cortex. We previously discovered that cerebellar granule cell-specific deletion of MEIS1 severely impairs cerebellar formation, and demonstrated that this phenomenon results from disruption of MEIS1-mediated regulation of cerebellar granule cell progenitor differentiation via transcription factor PAX6 and BMP signaling (Fig. 1, J. Neurosci 2018).

Although the above research represents the world's first detailed elucidation of MEIS1 function in the central nervous system, many aspects of transcription factor MEIS1 function in cerebellar development remain unknown.

We are currently investigating "the function of MEIS1 in cerebellar development beyond granule cells" and "research on developmental disorders caused by disruption of this function," primarily using mouse models, molecular biological and biochemical approaches, and bioinformatic analyses. We are also exploring "the distinct functions of individual MEIS1 isoforms" (https://doi.org/10.1101/2022.08.17.504235).

Through these studies, we hope to comprehensively elucidate the functions of MEIS1 in the central nervous system.

2. Elucidating the mechanisms controlling the timing of proliferation and differentiation in cerebellar granule cell progenitors

The cerebellum has long been considered important for motor function control, but research over the past decade has begun to report its involvement in higher functions such as social behavior and reward systems. Furthermore, like the cerebral cortex, the cerebellar cortex is a brain region that has expanded in cortical structure as evolution progressed toward primates.

Cerebellar volume increases almost proportionally with the number of cerebellar granule cells, and cerebellar granule cells have significantly increased in number in primates.

Since cerebellar granule cells have explosively increased in number during evolution, it has been predicted that a two-step neurogenesis mechanism involving secondary and tertiary proliferative neural progenitors, similar to the cerebral cortex, might exist, but its existence had not been clarified until recently.

In our previous research, we reported that there are two types of cerebellar granule cell progenitors (GCPs) in the mouse cerebellum: "undifferentiated ATOH1-positive GCPs (AT+GCPs)" and "slightly differentiated NEUROD1-positive GCPs (ND+GCPs)," and that AT+GCPs gradually transition to ND+GCPs during cerebellar development (AT-ND Transition) (EMBO J 2021). We also demonstrated that this AT-ND Transition is regulated by intercellular communication via Notch signaling between cerebellar granule cell progenitors (Fig. 2, eNeuro 2021).

Interestingly, ND+GCPs do not exist in reptiles or birds and are a cell type acquired in mammals. Based on these studies, we are currently investigating the behavior of each type of GCP during division and differentiation, as well as the evolutionary significance of the acquisition of ND+GCPs.

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