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Lineage dependent repulsion under the control of Dscam1 |
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Many neurons are precisely connected forming sophisticated neural circuits that enable our brain functions. On the other hand, columns are the higher-order morphological and functional units of the brain. A group of neurons gather to form individual columnar units, which are then precisely arranged to establish the brain. In the mammalian brain, the cerebral cortex is composed of columnar units. According to the 'radial unit hypothesis', columns are formed by the clonally related neurons that are produced from a common neural stem cell. However, it's not clear how far this hypothesis is applicable. In this study we investigated how radial units contribute to column formation in the fly brain.
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The 'radial unit hypothesis' was proposed to explain the mechanism of column formation in the mammalian cerebral cortex (left top). According to this hypothesis, columns are formed by the clonally related neurons that are produced from a common neural stem cell. The neurons of an individual radial unit are suggested to form a column. However, sister neurons actually undergo lateral dispersion during development, become sparsely distributed and are mixed with neurons derived from other stem cells. The roles of radial units may be more complex than previously proposed.
　Like the mammalian brain, the neurons of the same lineage are radially arranged, forming a radial cluster in the developing fly brain (right top). A group of neurons that derive from a neural stem cell was visualized by a technique called, 'mosaic analysis', and we found that the clustered neurons are tangentially dispersed later in development as observed in the mammalian bain. Furthermore, we observed that the neurons of the same lineage repel with each other and project to different columns, a process we named 'lineage dependent repulsion' (bottom). As you can see, the neurons that derive from the same stem cell project to distant columns in the brain (right bottom).
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We assumed that each neural stem cell and sister neurons that derive from the same stem cell are genetically labelled. We thus focused on the fly Dscam1 gene, which is homologous to the human Dscam, one of the responsible gene for Down syndrome. Dscam1 produces as many as 20,000 splice isoforms (top). The identical isoforms bind and repel with each other (left middle). We hypothesized that neurons of the same lineage are labelled with the same Dscam1 isoform that controls the lineage dependent repulsion (right middle). We demonstrated that Dscam1 is temporally expressed in neural stem cells and that the dauther neurons of the same stem cell express the same Dscam1 isoform. We developed a method called 'in situ RT-PCR' and visualized that a subset of Dscam1 isoforms are stochastically expressed in a subset of neural stem cells (bottom). A small number of Dscam1 isoforms are selected and expressed in neural stem cells, and as a result, neurons that derive from the same stem cell repel with each other.
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In normal brains, sister neurons that derive from the same neural stem cell project to distant columns (left). However, when Dscam1 function is disrupted, neurons of the same lineage project to the same column and the shape of the surrounding columns is disorganized (right). These results suggest that Dscam1 plays important roles in controlling lineage dependent repulsion and column formation.
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It was proposed that column formation depends on lineages of neurons. However, detailed mechanism of lineage dependent column formation was elusive. In this study, we demonstrated that lineage dependent repulsion under the control of Dscam1 plays important roles in column formation using the fly as a model system. Since the mechanisms of neurogenesis from a neural stem cell and the functions of Dscam genes are evolutionarily conserved from fly to human, the results of our study will be important in the future researches to understand the mechanisms of human brain development and neurodevelopmental disorders.
Liu, C., Trush, O., Han, X., Wang, M., Takayama, R., Yasugi, T., Hayashi, T., Sato, M.
Dscam1 establishes the columnar units through lineage-dependent repulsion between sister neurons in the fly brain.
Nature Communications 11, 4067 (2020).
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