Mechanism Behind Adult Neural Stem Cell Differentiation Revealed

Researchers from the Institute of Neurosciences have uncovered a crucial mechanism that allows adult neural stem cells to express genes responsible for maintaining their identity while simultaneously expressing genes for neuronal differentiation without conflicts in cellular activity. This discovery sheds light on how adult brain stem cells prepare themselves to respond readily to differentiation signals.

The study, led by Ángela Nieto, revealed that the key lies in the messenger RNAs (mRNAs) of stem cell genes leaving the nucleus to be translated into proteins, while the mRNAs of neuronal genes are retained within the nucleus. As Ainara González-Iglesias, the first author of the paper published in Nature Communications, explained, "When genes are transcribed, they generate messenger RNAs that are then translated into proteins, the effectors of cellular functions. For this process to occur, these messengers must leave the nucleus of the cell and go to the cytoplasm to be translated."

The researchers discovered that when stem cells need to differentiate into neurons, the mechanism operates in reverse. Nieto elaborated, "In this case, it is the messengers of the stem cell maintenance genes that are retained in the nucleus, preventing their translation into proteins." This mechanism not only resolves decision conflicts within cells but also primes the cellular machinery for immediate differentiation upon receiving the appropriate signal.

The study confirmed that the retention mechanism in the nucleus is associated with the lack of an RNA modification called methylation, which triggers the elimination of introns —fragments of messenger RNA that must be removed for proper nuclear export and translation of the messengers.

The team observed how the messenger RNA was retained in the nucleus using in situ hybridization, a technique that visualizes messenger RNA in tissues. González-Iglesias highlighted the importance of this technique, stating, "Although there are now sophisticated sequencing techniques, it was in situ hybridization what guided us to unveil the mechanism.