Molecular mechanisms of columnar unit formation by differential cell adhesion in the brain

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Columnar structure is a basic unit of the brain, but the mechanism of column formation remains largely unknown. In this study, we proposed the mechanism of column organization based on the differential level of adhesion between essential columnar neurons in the fly brain, regulated by cell adhesion molecules N-cadherin (N-cad) and Flamingo (Fmi). We revealed that column formation is initiated by three core neurons, R8, R7, and Mi1, and demonstrated that Ncad-dependent relative adhesiveness of these columnar neurons regulates their relative location within a column according to the differential adhesion hypothesis (DAH). First, we examined the level of Ncad in each of these neurons and found that columnar neurons contain more Ncad in the order of R7 > R8 > Mi1. Then, we decreased the level of Ncad in the most adhesive R7 neurons and found that the R7 expands from the center of the column to the peripheral area of the column. When Ncad level was reduced in R8 neurons, similar phenotype was observed: terminals of these neurons expanded and redirected to the peripheral area outside the column. In the contrary, overexpression of Ncad in less adhesive Mi1 neurons induced the redirection of these neurons toward the column center. Ncad overexpression in R8 neurons led to the extensive projection of R8 terminals to the center of the column. In addition, we established a mathematical model that confirms that the arrangement of core columnar neurons can be achieved solely by the differential adhesion between these core columnar neurons.