DISC1 - Function

Function

Many studies have provided insight into the normal function of the DISC1 protein, though much remains to be clearly defined. DISC1 is functionally involved in several processes that regulate neural development and brain maturation such as neuronal proliferation, differentiation, migration, cAMP signaling, cytoskeletal modulation, and translational regulation via various signaling pathways. Much of what is understood about the normal function of DISC1 has been uncovered through studies on zebrafish and mice as model organisms. In zebrafish, DISC1 is essential for forebrain development and GSK3/β-catenin signaling, while in mice the DISC1-GSK3 pathway regulates proliferation of neural progenitor cells in the cortex and adult dentate gyrus. This data suggests a direct DISC1 GSK3/β-catenin interaction.

DISC1 functions through a rich protein-protein interaction network, named the “DISC1 interactome” by researchers. Among its known interaction partners are 14-3-3ε, LIS1 and the PDE4B enzyme. DISC1 may play an important role in neuroplasticity via interactions with molecules of the cytoskeleton and centrosome, such as NUDEL and LIS1. The protein also enables the activity of dynein, a microtubule protein. Controlling transport of microtubules is involved in neuronal migration, neurite outgrowth, and axon formation.

DISC1 is highly expressed during critical periods of brain development, particularly in the embryonic ventricular and subventricular zones of the cortex, where neural progenitor cells are found. This localization suggests that DISC1 is an important regulator of embryonic and adult neurogenesis, and may regulate proliferation and/or differentiation. Levels of the protein in cycling neural progenitor cells affects whether they differentiate into neurons or remain as progenitors. Expression profile is highest in the hippocampus during development and remains highly expressed in the adult dentate gyrus and olfactory bulb, regions where adult neurogenesis is present. DISC1 has also been shown to regulate tempo of neuronal integration into the brain and guidance of positioning of new neurons.

Due to localization of the protein found at the synapse, DISC1 is also likely to play a key role in postsynaptic density, however this novel role is not yet fully understood.