the approach to know how does nerve system work
Molecular Function of DSCAM
DSCAM is a unique transmembrane protein that is responsible for “self-avoidance” in flies and mice (Hattori et al., Ann Rev Cell Dev, 2008). This cellular event is composed of two successive processes: recognition of allogenic cells and cancellation/masking of cell adhesion. Although it is known that the “recognition” process is elicited by the homophilic association of similar DSCAM variants, the molecular mechanism behind cancellation of cell adhesion remains unclear (Garrett et al., Proc Natl Acad Sci U S A, 2018).
In our recent study, we clarified that DSCAM accumulates at the detachment sites of endfeet and mediates neuronal delamination via the RapGEF2-Rap1-N-cadherin signaling cascade. (Arimura et al., Science Advances, 2020). Our manuscript highlights at least three major novel findings: 1) the involvement of DSCAM in the earliest molecular machinery of neuronal departure from the ventricular surface, 2) the suppression of N-cadherin by DSCAM-Rap1/RapGEF2 signaling cascade in neuronal detachment, and 3) the molecular mechanisms by which DSCAM cancels the activities of other cell adhesion molecules. This study provides important clues to understanding the molecular mechanisms by which newborn neurons detach from the ventricular surface upon their neuronal fate commitment. Our findings shed light on the key cellular machinery regulating proper cell tiling and avoiding allogenic neurite fasciculation, which is fundamental in normal neurogenesis and circuit formation.
The midbrain is a very important area involved in cognitive, emotional, and motor function control by secreting important neurotransmitters such as dopamine. In addition, the midbrain is considered to be the most developed in the very early stages of vertebrate brain evolution, preserving the molecular and morphological foundations that can form dense neural circuits. However, there are many unclear points about the developmental mechanisms of nerve cells in the midbrain.
Since many central nerve cells are located at different locations from where they are produced and where they actually function, they migrate after differentiating on the ventricular surface. Excitatory and inhibitory neurons in the cerebrum differentiate in completely different places and migrate to the cerebral cortex. On the other hand, in the mesencephalic nerve cells, various types of excitatory and inhibitory cells are produced ‘at the same time and in the same region’ from the limited ventricular surface and move to the same place, and this differentiation / migration control mechanism is mostly unknown. The phenomenon of excitatory and inhibitory cells differentiating and migrating in the same place is a phenomenon common to other regions composed of nerve nuclei such as pons and medulla oblongata, but the details have not been clarified. In addition, when neurons on the dorsal side of the midbrain (superior colliculus) are labeled in the short term, cells differentiated in the same region at the same time move and stop in each layer to form a rough layered structure. It is considered that there is an unexplained layer structure formation mechanism different from in the cerebrum and cerebellum. Thus, using the midbrain as a model system, now we trying to elucidate ‘how various differentiated nerve cells move to individual functioning places and stop.’