MicroRNA Blockage of a Single Protein Induces Fibroblasts to Differentiate into Neurons

Inhibition of the activity of PTB (polypyrimidine-tract-binding protein) by a specific microRNA (miRNA) is sufficient to induce fibroblasts to differentiate into functional neurons.

PTB is a ubiquitous RNA-binding protein. It was originally identified as a protein with a role in splicing but it is now known to function in a large number of diverse cellular processes including polyadenylation, mRNA stability, and translation initiation. Specificity of PTB function is achieved by a combination of changes in the cellular localization of this protein (its ability to shuttle from the nucleus to the cytoplasm is tightly controlled) and its interaction with additional proteins. These differences in location and trans-acting factor requirements account for the fact that PTB acts both as a suppressor of splicing and an activator of translation. Repression of PTB, which occurs during normal brain development via the action of miR-124, is sufficient to induce trans-differentiation of fibroblasts into functional neurons.

Investigators at the University of California, San Diego (USA) and their colleagues at Wuhan University (China) studied the transformation of fibroblasts to neurons in an in vitro system. They reported in the January 10, 2013, online edition of the journal Cell that repression of a single protein, PTB, was sufficient to induce transdifferentiation of fibroblasts into functional neurons.

Besides its traditional role in regulated splicing, they showed that PTB had a previously undocumented role in the regulation of microRNA functions, suppressing or enhancing microRNA targeting by competitive binding on target mRNA or altering local RNA secondary structure. Furthermore, they showed that a key event during neuronal induction was the relief of PTB-mediated blockage of microRNA action on multiple components of the REST complex, thereby de-repressing a large array of neuronal genes, including miR-124 and multiple neuronal-specific transcription factors, in non-neuronal cells. REST (RE1-silencing transcription factor) represses transcription by binding a DNA sequence element called the neuron-restrictive silencer element. This protein is also found in undifferentiated neuronal progenitor cells, and it is thought that this repressor may act as a master negative regular of neuron development.

These findings could have far-reaching implications for the development of new treatments for neurodegenerative diseases such as Huntington’s, Parkinson’s and Alzheimer’s.

“All of these diseases are currently incurable. Existing therapies focus on simply trying to preserve neurons or slow the rate of degeneration,” said senior author Dr. Xiang-Dong Fu, professor of cellular and molecular medicine at the University of California, San Diego. “People are working with the idea of replacing lost neurons using embryonic stem cells, but there are a lot of challenges, including issues like the use of foreign DNA and the fact that it is a very complex process with low efficiency. If we learn how to manipulate PTB, which appears to be a kind of master regulator, we might eventually be able to avoid some of these problems by creating new neurons in patients using their own cells adjacent deteriorating neurons.”

Related Links:
University of California, San Diego
Wuhan University