Narufumi Kameya

The mechanisms by which environmental signals induce permanent developmental changes remain a fundamental biological problem. We investigated sea star metamorphosis, where microbial biofilms induce a total body plan reorganization. Using systems biology and functional assays, we identified a three-tiered signaling cascade: sensing, conversion, and execution. The immune adaptor MyD88 senses microbes, while MAPK proteins convert this signal into a retinoic acid developmental cue. An amyloid precursor protein (APP)-centered module acts as the irrevocable commitment gateway, stabilized by a positive feedback loop to ensure irreversibility. Remarkably, the genes driving this transition overlap with human pathways for Alzheimer’s disease and ADHD/Autism. By defining this ancient neuro-immune axis in an echinoderm adult body plan similar to the chordate head, our study establishes sea star metamorphosis as a model for understanding the evolutionary origins of human neurological disorders from the evolutionary developmental pathology perspective.

Background: The mammalian cerebrum has changed substantially during evolution. Neurons and glial cells have increased, and the cerebrum has expanded and folded. Although these evolutionary changes are believed to be important for acquiring higher cognitive functions, the molecular mechanisms underlying the development and evolution of the mammalian cerebrum are not fully understood. This is partially due to the difficulty in analyzing these mechanisms using only mice. Summary: To overcome this limitation, we developed genetic manipulation techniques for the cerebrum of gyrencephalic carnivore ferrets. Gene knockout in the ferret cerebrum was achieved using the CRISPR/Cas9 system. Key Messages: This review highlights recent research from our lab and others on the mechanisms underlying the development and evolution of cortical folds using ferrets.

The functional significance of the morphological and genetic changes that occurred in the brain during evolution is not fully understood. Here we show the relationships between evolutionary changes of the brain and glymphatic circulation. We establish a mathematical model to simulate glymphatic circulation in the cerebral hemispheres, and our results show that cortical neurons accumulate in areas of the cerebral hemispheres where glymphatic circulation is highly efficient. We also find that cortical folds markedly enhance the efficiency of glymphatic circulation in the cerebral hemispheres. Furthermore, our in vivo study using ferrets reveals sulcus-dominant cerebrospinal fluid (CSF) influx, which enhances the efficiency of glymphatic circulation in the enlarged cerebral hemispheres of gyrencephalic brains. Sulcus-dominant CSF influx is mediated by preferential expression of aquaporin-4 in sulcal regions, and similar expression patterns of aquaporin-4 are also found in human cerebral hemispheres. These results indicate that evolutionary changes in the cerebral hemispheres are related to improved efficiency of glymphatic circulation. It seems plausible that the efficiency of glymphatic circulation is an important factor determining the evolutionary trajectory of the cerebral hemispheres.

The development and evolution of mammalian higher cognition are represented by gyrification of the laminar cerebral cortex and astrocyte development, but their mechanisms and interrelationships remain unknown. Here, we show that localized astrogenesis plays an important role in gyri formation in the gyrencephalic cerebral cortex. In functional genetic experiments, we show that reducing astrocyte number prevents gyri formation in the ferret cortex, while increasing astrocyte number in mice, which do not have cortical folds, can induce gyrus-like protrusions. Morphometric analyses demonstrate that the vertical expansion of deep pallial regions achieved by localized astrogenesis is crucial for gyri formation. Furthermore, our findings suggest that localized astrogenesis by a positive feedback loop of FGF signaling is an important mechanism underlying cortical folding in gyrencephalic mammalian brains. Our findings reveal both the cellular mechanisms and the mechanical principle of gyrification in the mammalian brain.