Molecular signal turns on stem cells in brain
Researchers have succeeded in identifying how a molecule in the brain "turns on" stem cells at different stages in brain development.
In a study published in the journal Neuron, researchers at Karolinska Institutet in Sweden show how the molecule TGF-beta acts as a signal regulating nerve stem cells at different stages of brain development — knowledge that may be significant in future pharmaceutical reearch.
The human brain consists of thousands of different types of nerve cells that form from what are described as immature stem cells.
It was known that neural stem cells change as the human brain develops and ages, and that one type of stem cell can produce multiple types of nerve cells.
Up until now though, how neural stem cell identity and regulation occurred was not well understood. But with this study, says Johan Ericson, Professor of Developmental Biology, and study leader: "TGF-beta functions as an important time signal controlling when a stem cell should stop producing one type of nerve cell and start producing another, which also gradually limits a stem cell's future developmental capacity."
Researchers show how TGF-beta can be used in stem cell cultures to mass-produce nerve cells — which in turn produce the signalling substance serotonin.
Today the brain's serotonin system is a known target for treating depression. But now Karolinska researchers believe it may be possible to use stem cell signals in pharmaceutical development and begin generation of new neural cell growth.
Johan Ericson: "This is the first known signalling molecule to regulate the potential of neural stem cells. With a better understanding of how that potential is regulated, it might be possible to broaden the development spectrum of ageing stem cells and allow them to regain their capacity to produce cell types once produced during earlier brain development stages. In the long-term, this could be relevant for future treatment of neurodegenerative disease."
•Tgfβ is a devoted switch signal in temporal patterning of the vertebrate brain
•Tgfβ signaling regulates neural stem cell potential
•Tgfβ regulates the overall lifespan of an Nkx2.2+ temporal differentiation lineage
•Tgfβ bypasses early neurogenesis and induces late-born neurons in stem cell cultures
How the sequential specification of neurons and progressive loss of potency associated with aging neural progenitors are regulated in vertebrate brain development is poorly understood. By examining a temporal differentiation lineage in the hindbrain, we here identify Tgfβ as a switch signal that executes the transition between early and late phases of neurogenesis and concurrently constrains progenitor potency. Young progenitors have inherent competence to produce late-born neurons, but implementation of late-differentiation programs requires suppression of early identity genes achieved through temporally programmed activation of Tgfβ downstream of Shh signaling. Unexpectedly, we find that sequentially occurring fate-switch decisions are temporally coupled, and onset of Tgfβ signaling appears thereby to impact on the overall lifespan of the temporal lineage. Our study establishes Tgfβ as a regulator of temporal identity and potency of neural stem cells, and provides proof of concept that Tgfβ can be applied to modulate temporal specification of neurons in stem cell engineering.
Publication: "Tgfβ signaling regulates temporal neurogenesis and potency of neural stem cells in the CNS", José M. Dias, Zhanna Alekseenko, Joanna M. Applequist and Johan Ericson, Neuron online 13 November 2014.
The research was funded by grants from the Swedish Foundation for Strategic Research (SSF), Knut and Alice Wallenberg Foundation, Swedish Research Council, Swedish Cancer Society and Swedish Brain Foundation.
Return to top of page