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REST's Repressive Activities Determine Neuronal Cell Development

By Thaddeus Schug
December 2009

Gail Mandel
Gail Mandel
(Photo courtesy of Bruce Forster)

On November 13, Distinguished Lecturer Gail Mandel, Ph.D., came to NIEHS to talk about her research, which is defining the gene regulatory mechanisms involved in cell differentiation and specialization. Mandel, a recent inductee into the National Academy of Sciences, presented a seminar titled "Repression Mechanisms and Neuronal Phenotype." The lecture was co-hosted by NIEHS Principal Investigators Serena Dudek, Ph.D. and Paul Wade, Ph.D.

Mandel,( NIEHS a senior scientist at the Oregon Health and Science University (OHSU) Vollum Institute in Portland and an investigator with the Howard Hughes Medical Institute, said, "Understanding what makes a neuron different from all other types of cells is key to establishing how cell identity is established and maintained." She explained that identifying the key regulatory proteins in cells should help efforts to reprogram mature cells into stem cells or other cell types. Reprogramming could someday allow the recapitulation of disease processes from patients' tissue or the creation of new tissues, such as insulin-producing cells from the pancreas.

Mandel became interested in neuronal development while investigating proteins that control gene expression of the sodium channel in neurons. She expected to find an activating protein, but, "Instead, I found that nervous system gene expression is sustained in a very unusual way," she continued. Mandel demonstrated that neuronal specificity is defined not by an activator, but by the absence of an inhibitor protein that she found in 1995 and named RE1-silencing transcription factor or REST. When REST is absent in neuronal cells, neuronal genes are expressed. REST's presence in nonneuronal cells represses neuronal genes. Employing several genetic techniques, her group has revealed that REST silences 2,000-4,000 neuronal genes in nonneuronal cells, making it a master regulator of neuronal identity.

Utilizing gene trap reporter mouse models and embryonic stem cells, Mandel's group has established how the REST repressor complex is regulated during normal development. She said that REST's repressive activities are important during nervous system development, when stem cells differentiate into the various cells that ultimately make up the nerves, spinal cord and brain. REST is present in cells slated to become neurons, yet it keeps neuron genes turned off. At some point, REST disappears when the cell matures and neuron genes are expressed.

"REST keeps DNA less compact in developing neuronal cells than in nonneuronal cells, where REST acts on DNA like a clamp, like a much stricter parent," she commented. Mandel is studying REST repression mechanisms and how REST vanishes at the right time in development to allow nerve cells to form and express their genes.

Mandel concluded her presentation by discussing how REST regulates the expression of a family of micro RNAs (miRNA). She noted that in nonneuronal cells and neural progenitors, REST inhibits the expression of miR-124a , a brain-specific miRNA, allowing the persistence of nonneuronal transcripts. As progenitors differentiate into mature neurons, REST leaves the miR-124a gene loci, and nonneuronal transcripts are degraded selectively. She concluded that the combined transcriptional and posttranscriptional consequences of REST action maximize the contrast between neuronal and nonneuronal cell phenotypes.

Co-host Dudek noted that both she and Wade independently nominated Mandel to be an NIEHS Distinguished Lecturer, a rarity that speaks to the quality of Mandel's work. "Mandel's research is impressive because it encompasses such a broad spectrum of interest in molecular biology," Dudek said.

(Thaddeus Schug, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)

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