How do neurons become neurons? They all begin as stem cells, undifferentiated and with the potential to become any cell in the body.
Until now, however, exactly how that happens has been somewhat of a scientific mystery. Working with human embryonic stems cells in petri dishes, scientists discovered a new pathway that plays a key role in cell differentiation. The findings appear in the journal Cell.
When stem cells begin to differentiate, they form precursors: neuroectoderms that have the potential to become brain cells, such as neurons; or mesendoderms, which ultimately become cells that comprise organs, muscles, blood and bone.
Researchers discovered a number of steps when they labeled the PAN (Primary cilium, Autophagy Nrf2) axis. This newly identified pathway appears to determine a stem cell's final form.
"The PAN axis is a very important player in cell fate decisions," explained Jang. "G1 lengthening induces cilia protrusion and the longer those cellular antennae are exposed, the more signals they can pick up."
For some time, scientists have known about Gap 1 (G1), the first of four phases in the cell cycle, but they weren't clear about its role in stem cell differentiation. Researchers demonstrate that in stem cells destined to become neurons, the lengthening phase of G1 triggers other actions that cause stem cells to morph into neuroectoderms.
During this elongated G1 interval, cells develop primary cilia, antennalike protrusions capable of sensing their environment. The cilia activate the cells' trash disposal system in a process known as autophagy.
Another important factor is Nrf2, which monitors cells for dangerous molecules such as free radicals -- a particularly important job for healthy cell formation.
The work showed that levels of Nrf2 begin to decline during the elongated G1 interval. This is significant, because Nrf2 doesn't usually diminish until the cell has already started to differentiate.
"We thought that, under the same conditions if the cells are identical, that both would differentiate the same way, but that is not what we found," author said. "Cell fate is controlled by G1 lengthening, which extends cilia's exposure to signals from their environment. That is one cool concept."
Unraveling first steps in stem cell differentiation into neurons
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