Mechanistic insight into the role of mTOR signalling in neurogenesis and neurodevelopmental diseases

The mechanistic target of rapamycin (mTOR) pathway senses growth factors, nutrients and energy levels to control anabolic cellular processes. mTOR signalling is a key regulator of neurogenesis and mTOR pathway activation is associated with epilepsy and autism syndromes. The molecular mechanism by which the mTOR pathway regulates neurogenesis is unknown. We previously identified the gene Unkempt in a genetic screen for novel mTOR pathway components that regulate neurogenesis in Drosophila. We have recently been investigating the role of Unkempt in mTOR signalling in mammalian neurogenesis. mTOR is a serine/threonine kinase and we find that Unkempt phosphorylation is dependent on mTOR activity in human and murine neuroblastoma cells and in murine primary neurons. In vitro experiments show that Unkempt is directly phosphorylated by mTOR. We have identified specific amino acids in Unkempt whose phosphorylation is mTOR dependent. We also find that Unkempt is a key regulator of neurogenesis in the developing mammalian cortex. mTOR activation causes defects in the development and migration of neural progenitors and overexpression of Unkempt rescues these neurodevelopmental defects. Unkempt is therefore a novel mTOR substrate that regulates mammalian neurogenesis. These findings provide new insight into the regulation of neurogenesis by mTOR signalling and its role in neurodevelopmental disease.