GSK-3 (glycogen synthase kinase-3) is a serine-threonine kinase that consists of two family members in mammals, α and β, which share 98% sequence identity in their kinase domains. The β-isoform has recently been identified as a mediator of neurogenesis under the control of DISC1, a protein encoded by a gene implicated in schizophrenia susceptibility. GSK-3 has also been shown to be involved in regulation of embryonic stem cell self-renewal – GSK3 inhibitors help in maintenance of pluripotency.
A new study from researchers at the University of North Carolina at Chapel Hill School of Medicine has now shown that GSK-3 is a key regulator of neural stem cell proliferation and differentiation. Neural stem cells progress through different stages – neural epithelial cells, radial progenitor cells and intermediate neural precursors – and radial progenitor cells are particularly important because they are thought to provide the majority of the neurons of the developing brain and to give rise to all the cellular elements of the brain. The researchers used a conditional knockout in a mouse model, deleting both isoforms of GSK-3 during the radial progenitor phase of development. This resulted in locking the radial progenitor cells in a proliferative state, with no generation of mature neurons. The next step is to determine whether switching GSK-3 back on can stimulate differentiation, leading to an increased number of mature neurons. The researchers suggest that understanding the role of GSK-3 in neurogenesis could have implications for patients with neuropsychiatric conditions such as schizophrenia, depression and bipolar disorder.
The study is published in the journal Nature Neuroscience.