A Key to New Neuron Birth in the Young Brain

Different cell types in the brain are vulnerable in different degenerative brain diseases – Alzheimer’s, Parkinson’s and multiple sclerosis, for instance.

Biomedical researchers are aiming to develop new strategies for fighting these diseases by finding ways to coax vulnerable cells to survive, or if they die, to replace them with the same type of cells.

The brain is composed of not only signaling neurons, but also glial cells, which insulate and protect neurons and provide structural support. Both neurons and glial cells arise from neural stem cells, and some types of neurons and glial cells are born throughout life from stem cells in the adult brain.

This new paradigm – that the adult brain has the plasticity to grow new cells – has only gained ascendance in the last decade or so.

Arturo Alvarez-Buylla

UCSF researchers have long been at the center of successful efforts to identify and characterize stem cells in the brain. Now, as reported in the Feb. 11 online edition of Nature, UCSF Department of Neurological Surgery researchers led by Daniel Lim, MD, PhD, and Arturo Alvarez-Buylla, PhD, have found a genetic switch that is required for neural stem cells to become neurons.

Daniel Lim

In young mice, neural stem cells lacking a gene product called Mll1 can still proliferate and survive, but they do not form neurons as they normally would, the researchers discovered. Cells without Mll1 instead give rise only to glial cells.

For neural stem cells to form neurons, their daughter cells must turn on, or express, certain sets of genes, while repressing others. Patterns of gene expression – including the pattern required to give rise to neurons – are established, in part, by how DNA on chromosomes is packaged together with proteins to form a structure called chromatin.

Mll1 is part of a family of enzymes that modify chromatin to either activate or silence gene expression. These so-called epigenetic modifications can be passed on through cell division, providing a cell with a kind of memory of its specialized identity and the functions it is fated to perform.

In the Nature paper, the authors provide evidence that Mll1 operates in part by activating a downstream gene called Dlx2. UCSF researcher John Rubenstein, MD, PhD, previously showed that Dlx genes are essential for the development of inhibitory neurons in the forebrain. Mll1 activates Dlx2 expression by chemically modifying the chromatin, marking the Dlx2 gene for persistent expression.

Lim began the work in the lab of Alvarez-Buylla, who has been a mentor to Lim. Alvarez-Buylla has conducted seminal experiments to identify stem cells in a region of the brain called the subventricular zone, and is among those who helped to clearly demonstrate that new neurons can indeed be born in the adult brain throughout life.

After completing a residency in neurosurgery at UCSF, Lim joined the faculty and started his own laboratory last year. Lim, Alvarez-Buylla and Rubenstein also are faculty members of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

The new studies that Lim now leads are in the realm of basic biology, but he is a practicing neurosurgeon and his goal is to see his work applied in the clinic. He is hopeful that a growing understanding of the molecular determinants of cell fate in the brain will one day enable manipulation of brain cells. The goal is to reprogram the cells to specific cell fates, thus guiding the formation of new cells to replace or augment those lost to degenerative brain disease.

“Dr. Alvarez-Buylla and I both strongly believe that understanding the basic biology of neural stem cell regulation is key to unlocking their therapeutic potential,” Lim says. “I believe that these findings about how neural stem cells turn on specific genes for the production of new neurons will lead to a greater ability to someday repair the diseased or damaged brain.”

Chromatin Remodelling Factor Mll1 Is Essential for Neurogenesis from Postnatal Neural Stem Cells


Daniel A. Lim, Yin-Cheng Huang, Tomek Swigut, Anika L. Mirick, Jose Manuel Garcia-Verdugo, Joanna Wysocka, Patricia Ernst and Arturo Alvarez-Buylla
Nature (Published Online Feb. 11, 2009)
Abstract

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UCSF Today, Aug. 22, 2008

Daniel Lim, MD, PhD
UCSF Biomedical Sciences Graduate Program

Arturo Alvarez-Buylla, PhD
UCSF Department of Neurological Surgery

UCSF Department of Neurological Surgery

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF