A Brief History of Adherons: The Discovery of Brain Exosomes

Although exosomes were first described in reticulocytes in 1983, many people do not realize that similar vesicles had been studied in the context of muscle and nerve, beginning in 1980. At the time of their discovery, these vesicles were named adherons, and they were found to play an important role in both cell–substrate and cell–cell adhesion. My laboratory described several molecules that are present in adherons, including heparan sulfate proteoglycans (HSPGs) and purpurin. HSPGs have since been shown to play a variety of key roles in brain physiology. Purpurin has a number of important functions in the retina, including a role in nerve cell differentiation and regeneration. In this review, I discuss the discovery of adherons and how that led to continuing studies on their role in the brain with a particular focus on HSPGs.

Developmental neurobiology of hydra, a model animal of cnidarians

Hydra belongs to the class Hydrozoa in the phylum Cnidaria. Hydra is a model animal whose cellular and developmental data are the most abundant among cnidarians. Hence, I discuss the developmental neurobiology of hydra. The hydra nerve net is a mosaic of neural subsets expressing a specific neural phenotype. The developmental dynamics of the nerve cells are unique. Neurons are produced continuously by differentiation from interstitial multipotent stem cells. These neurons are continuously displaced outwards along with epithelial cells and are sloughed off at the extremities. However, the spatial distribution of each neural subset is maintained. Mechanisms related to these phenomena, i.e., the position-dependent changes in neural phenotypes, are proposed. Nerve-net formation in hydra can be examined in various experimental systems. The conditions of nerve-net formation vary among the systems, so we can clarify the control factors at the cellular level by comparing nerve-net formation in different systems. By large-scale screening of peptide signal molecules, peptide molecules related to nerve-cell differentiation have been identified. The LPW family, composed of four members sharing common N-terminal L(or I)PW, inhibits nerve-cell differentiation in hydra. In contrast, Hym355 (FPQSFLPRG-NH3) activates nerve differentiation in hydra. LPWs are epitheliopeptides, whereas Hym355 is a neuropeptide. In the hypostome of hydra, a unique neuronal structure, the nerve ring, is observed. This structure shows the nerve association of neurites. Exceptionally, the tissue containing the nerve ring shows no tissue displacement during the tissue flow that involves the whole body. The neurons in the nerve ring show little turnover, although nerve cells in all other regions turn over continuously. These associations and quiet dynamics lead me to think that the nerve ring has features similar to those of the central nervous system in higher animals.

Pattern of differentiated nerve cells in hydra is determined by precursor migration

The nervous system of the fresh water polyp hydra is built up as a nerve net spread over the whole body, with higher densities in the head and the foot. In adult hydra, as a result of continuous growth, new nerve cell differentiation takes place continuously. The pattern of nerve cell differentiation and the role of nerve cell precursor migration in establishing the pattern have been observed in vivo by vitally labelling precursor cells with DiI. The results indicate that nerve cell precursors arise directly from stem cells, complete a final cell cycle and divide, giving rise to two daughter cells, which differentiate into nerve cells. A subpopulation of the nerve cell precursors are migratory for a brief interval at the onset of the terminal cell cycle, then complete the cell cycle and divide at the site of differentiation. Labelling small patches of tissue in the head, body column and peduncle/foot with DiI indicated that formation of nerve cell precursors was nearly constant at all three positions. However, at least half of the labelled precursors in the body column migrated to the head or foot before differentiating; by contrast, precursors in head and foot differentiated in situ without significant migration. This redistribution leads to a net increase of nerve cell precursors in head and foot compared to body column and thus to the higher density of nerve cells in these regions.