The ability to generate neural precursor cells that then differentiate into neurons and glia in the nervous system is fundamental to human development. Biologists know that a breakdown in the molecular pathways controlling neural precursor biology can lead to severe disorders, including autism, neural-tube defects, epilepsy, anophthalmia, retarded growth, and sensorineural deafness.
Biologists have long wanted to understand how neural precursor cells self-renew and generate their progeny in a highly organized fashion, and now a team of researchers at Sanford-Burnham has discovered a pathway critical for these processes. At its heart is a transcription factor called SOX2, which the scientists found is required to maintain optimal levels of a protein called LIN28, previously implicated in reprogramming along with SOX2 itself. Surprisingly, LIN28 was found to be the major downstream effector of SOX2 for the self-renewal of neural precursors. On the other hand, by maintaining optimum levels of LIN28, the SOX2 protein indirectly suppresses a small RNA molecule called lethal-7 (also known as “let-7”) microRNA.
Why is this important? Because scientists have found that the major function of the let-7 family of genes in vertebrates – which is conserved across species – is to halt cell differentiation and suppress tumors. In fact, expression levels of let-7 genes are low in human cancers and cancer stem cells. So while expression of let-7 appears important to prevent cancer cells from proliferating, it’s not such a good thing during development when cells need to self-renew.
“We have discovered that SOX2 regulates LIN28 expression and, subsequently, the level and activity of let-7 microRNAs,” said Alexey Terskikh, Ph.D., whose lab at Sanford-Burnham made the discovery. Their study suggests that LIN28 is a direct target of SOX2, he added. “Our findings suggest previously unsuspected roles for the SOX2-LIN28/let-7 pathway in regulating neural precursor proliferation and neurogenesis.”
Mapping this molecular pathway paves the way toward finding ways to regulate the function of let-7 microRNA in specific tissues, Dr. Terskikh said. Let-7 microRNAs help orchestrate when neuroblasts develop into mature neurons, so finding a way to manipulate the expression of let-7 microRNAs could mark an important step in restoring neural precursor cell biology where it’s broken down.
Another target for potential therapeutics could be the SOX2 gene itself, Dr. Terskikh said. His team has discovered a novel epigenetic mechanism by which SOX2 controls the activity of LIN28, so that finding gives researchers a mechanistic understanding of the process and “opens up a novel way to manipulate neural stem cells,” said Dr. Terskikh.
“There are many critical questions to be solved,” he said of the next steps in his team’s research. “It will be important to fully determine the function of LIN28 and let-7 in the regulation of neurogenesis, and to examine the role of individual let-7 microRNAs in modulating the proliferation and/or differentiation of neural stem cells.” Most of his lab’s work so far has been conducted in vitro, Dr. Terskikh added. “It will be critical to investigate the role of LIN28 and individual let-7 microRNAs in vivo – for instance in the maintenance of adult hippocampal neurogenesis.”
The paper by Dr. Terskikh and his colleagues, SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors, was published this week in the early edition of the Proceedings of the National Academy of Sciences.
Flavio Cimadamore, Alejandro Amador-Arjona, Connie Chen, Chun-Teng Huang, and Alexey V. Terskikh (2013). SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors Proceedings of the National Academy of Sciences of the United States of America DOI: 10.1073/pnas.1220176110