Newly discovered protein makes sure brain development isn't 'botched'

May 22, 2012, Johns Hopkins University

(Medical Xpress) -- Johns Hopkins scientists have discovered a protein that appears to play an important regulatory role in deciding whether stem cells differentiate into the cells that make up the brain, as well as countless other tissues. This finding, published in the April Developmental Cell, could eventually shed light on developmental disorders as well as a variety of conditions that involve the generation of new neurons into adulthood, including depression, stroke, and posttraumatic stress disorder.

Researchers have long known that a small group of proteins called Notch plays a in helping the present in to develop into the variety of cells present throughout the body, including those that make up the brain, blood, kidneys and muscles.

“Notch signaling is involved in almost all aspects of development,” explains study leader Valina Dawson, Ph.D., a professor in the departments of Neurology, Neuroscience, and Physiology and co-director of the Stem Cell and Neuroregeneration Programs at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine.

However, she says, even for researchers who have been studying Notch for decades, how this small group of proteins manages the development of such a diverse array of tissues and organs in the body remains unknown. It’s a pivotal mystery to solve, Dawson adds, since problems in Notch signaling seem to be involved in various cancers, Alzheimer’s disease, juvenile and many other health problems.

In their new study, Dawson and her colleagues shed light on one way Notch proteins might be regulated, through a protein they recently discovered in the lab. This protein seemed to be involved in development, but at first, the researchers didn’t know its function.

To determine what purpose this protein serves in cells, Dawson, postdoctoral fellow Zhikai Chi, M.D., Ph.D., and their colleagues started by trying to determine what other proteins it’s able to bind to. By adding the mystery protein to cell cultures that expressed a variety of other proteins, they determined that the unknown protein altered cellular activity in those expressing Notch.

Since Notch is involved intimately in determining the fate of brain precursor cells, driving neural to proliferate and determining whether they become or supporting cells known as glia, the researchers next examined how this mystery protein affected brain development in mouse embryos. They found that by increasing expression of the unknown protein, more neurons developed in certain parts of the developing brain, including the intermediate zone and cortical plate. In contrast, decreasing expression led to fewer neurons. Taken together, Dawson says, these experiments provided even more evidence that their unknown protein was somehow influencing Notch.

To determine exactly how the mystery protein was affecting Notch, the researchers examined the effect of the protein on neural stem cells in the process of differentiating into mature cell types. Increasing the amount of the unknown protein swayed development as if Notch wasn’t working. Since the unknown protein appeared to prevent Notch from acting on , the researchers named it Botch for “blocks Notch.”

With Botch’s role now clear, the researchers turned next to the mechanism behind how this protein exerts its influence. A series of experiments suggests that Botch interacts with Notch in the Golgi body, a cellular organelle involved in modifying proteins. For Notch to act in development, an immature version of this protein needs to be cleaved in order for the to be rearranged. Botch appears to prevent this pivotal modification from taking place, reducing the amount of mature Notch available to do its job.

Because Botch appears to play such an important role in regulating Notch, Dawson says, it could be involved in a number of diseases in which the generation of new neurons is misregulated. She and her colleagues are already performing some preliminary experiments to determine whether Botch expression might vary from the norm in diseases such as , which has been linked to a decrease in neurogenesis in the brain’s hippocampus. Eventually, researchers might be able to develop drugs that act on Botch to restart stalled neurogenesis, potentially treating depression and other diseases in which a lack of neurogenesis is thought to play a role.

“There are potentially some very large neurological problems that could be addressed through changing Botch activity,” Dawson says.

Explore further: Key regulator of nervous system development works by blocking signaling protein

Related Stories

Key regulator of nervous system development works by blocking signaling protein

April 29, 2011
Neuroepithelial stem cells, the early progenitors for much of the nervous system, need to maintain a keen sense of direction in order to properly manage replication, migration and maturation. These cells are highly polarized, ...

Penn researchers describe key molecule that keeps immune cell development on track

August 8, 2011
In the latest issue of Nature, researchers at the Perelman School of Medicine at the University of Pennsylvania clarify the role of two proteins key to T-cell development. They found that one well-known protein called Notch ...

Recommended for you

Research reveals atomic-level changes in ALS-linked protein

January 18, 2018
For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases ...

Fragile X finding shows normal neurons that interact poorly

January 18, 2018
Neurons in mice afflicted with the genetic defect that causes Fragile X syndrome (FXS) appear similar to those in healthy mice, but these neurons fail to interact normally, resulting in the long-known cognitive impairments, ...

How your brain remembers what you had for dinner last night

January 17, 2018
Confirming earlier computational models, researchers at University of California San Diego and UC San Diego School of Medicine, with colleagues in Arizona and Louisiana, report that episodic memories are encoded in the hippocampus ...

Recording a thought's fleeting trip through the brain

January 17, 2018
University of California, Berkeley neuroscientists have tracked the progress of a thought through the brain, showing clearly how the prefrontal cortex at the front of the brain coordinates activity to help us act in response ...

Midbrain 'start neurons' control whether we walk or run

January 17, 2018
Locomotion comprises the most fundamental movements we perform. It is a complex sequence from initiating the first step, to stopping when we reach our goal. At the same time, locomotion is executed at different speeds to ...

Miles Davis is not Mozart: The brains of jazz and classical pianists work differently

January 16, 2018
Keith Jarret, world-famous jazz pianist, once answered in an interview when asked if he would ever be interested in doing a concert where he would play both jazz and classical music: "No, that's hilarious. [...] It's like ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.