Work-life balance: Brain stem cells need their rest, too

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Work-life balance: Brain stem cells need their rest, too

http://www.eurekalert.org/pub_releases/2010-07/si-wbb062910.php

LA JOLLA, CA—Stem cells in the brain remain dormant until called upon to divide

and make more neurons. However, little has been known about the molecular guards

that keep them quiet. Now scientists from the Salk Institute for Biological

Studies have identified the signal that prevents stem cells from proliferating,

protecting the brain against too much cell division and ensuring a pool of

neural stem cells that lasts a lifetime.

The research, which will be published in the July 1 issue of Cell Stem Cell,

highlights the importance of bone morphogenetic factor protein (BMP) signaling

for the maintenance of a neural stem cell reservoir throughout adult life and

may provide the key to understanding the interplay between exercise, aging and

neurogenesis.

Adult neural stem cells in the hippocampus—a memory hub of the brain—sprout new

brain cells throughout life. This particular area of the brain, one of only two

for which neurogenesis has been clearly shown, is particularly vulnerable to

age-related degeneration. Regular physical exercise not only slows the shrinking

of aging hippocampi but also improves learning and memory in mature adults.

" This study provided us with very important insights into how adult stem cells

are regulated, says senior author Fred H. Gage, Ph.D., a professor in the

Laboratory for Genetics at the Salk Institute and the Vi and Adler Chair

for Research on Age-Related Neurodegenerative Diseases. " Going forward, we can

start to tinker with this mechanism to understand how exercise influences the

aging brain. "

During the process of neurogenesis, neurons-to-be pass through several distinct

stages, including cell birth, fate determination, survival, integration, and

acquisition of functional properties.

" Each stage is driven by a complex interplay between intrinsic mechanisms and

environmental cues, " says co-first author Helena Mira, formerly a post-doc in

the Gage laboratory and now an assistant professor in the Department of Cell

Biology and Development at the III Health Institute & #8232;in Madrid. " We

already knew a lot about fate choice and differentiation, but it was unclear how

neural stem cells decided to divide or not in the first place. "

Using their observation that quiescent neural stem cells express the BMP

receptor 1A as a starting point, Mira and her collaborators investigated the

role of BMP signaling in regulating the proliferation of stem cells located in

the hippocampus, one of two brain regions harboring neural stem cells.

They found that BMP signaling, which is triggered by the interaction of BMPs

with their receptors, is inactive in most proliferating cells, whereas it is

active in non-dividing cells, including quiescent stem cells and differentiated

neurons. Unlike stem cells, mature neurons express BMP receptor 1B, which will

be the focus of future studies.

Experiments with cultured neural stem cells confirmed that it was indeed BMP

that kept them quiet. BMP's anti-proliferative effect was blocked when BMP was

replaced with a protein known as Noggin, which binds and inactivates members of

the BMP family.

The researchers observed the same effect when they delivered Noggin directly

into the brains of adult mice. Here, too, Noggin successfully interfered with

BMP signaling and raised quiescent stem cells out of their slumber. After one

week, those neural stem cells had started dividing and their offspring were well

on their way to becoming neurons.

When neural stem cells were forced to proliferate over prolonged periods of

time, however, the pool of active neural stem cells was depleted, suggesting to

Gage and his team that quiescence functions as a protective mechanism that

counteracts stem cell exhaustion and bursts of dividing cells, which could lead

to tumors.

" It tells you how finely this process is regulated, " says Mira. " BMP ensures a

sufficiently big population of quiescent stem cells that can feed into the

system when called upon. "

BMP may also be the linchpin that links exercise, aging and neurogenesis. " As we

age, the number of new neurons declines but physical exercise brings that number

back up, " says Gage. " Our findings raise the possibility that the BMP signal

becomes dominant over time, forcing neural stem cells deeper into quiescence and

thus making it harder to generate new brain cells. "

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Researchers who also contributed to the study include Zoraida Andreu, a San

Emeterio, and Hortigüela at the III Health Institute, Madrid,

Hoonkyo Suh, Antonella Consiglio and Kinichi Nakashima at the Salk Institute for

Biological Studies, La Jolla, María Ángeles Marqués-Torrejón and Isabel Fariñas

at the University of Valencia, Spain, D. Chichung Li, Dilek Colak and Magdalena

Götz at the Helmholtz Center Munich, Germany, as well as Sebastian Jessberger at

the ETH Zurich, Switzerland.

The work was in part funded by the Deutsche Forschungsgemeinschaft, the Programa

Ramon y Cajal from the Spanish Ministerio de Educacion y Ciencia, the Centro de

Investigación Príncipe Felipe, and the Helmholtz Association.

About the Salk Institute for Biological Studies & #8232;

The Salk Institute for Biological Studies is one of the world's preeminent basic

research institutions, where internationally renowned faculty probe fundamental

life science questions in a unique, collaborative, and creative environment.

Focused both on discovery and on mentoring future generations of researchers,

Salk scientists make groundbreaking contributions to our understanding of

cancer, aging, Alzheimer's, diabetes, and infectious diseases by studying

neuroscience, genetics, cell and plant biology, and related disciplines. Faculty

achievements have been recognized with numerous honors, including Nobel Prizes

and memberships in the National Academy of Sciences. Founded in 1960 by polio

vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit

organization and architectural landmark.

The Salk Institute proudly celebrates five decades of scientific excellence in

basic research.