A big surprise:Young nerve cells can rewind their developmental clocks

[Guest guest]

As many of you know that have been members for awhile -I question

the links between the gray matter, myelin -and the links to PUFA

supplementation in our children.

I just read an interesting paper which is very exciting for what

this may mean for the future of many with neurological conditions

including apraxia. As many of you know -the one gene found linked

to apraxia is the FoxP2 gene located on chromosome 7, -read about

what was just discovered with the Foxg1 gene " a finding that could

open another door to tissue replacement therapy in the central

nervous system "

Public release date: 1-Jan-2004

Contact: Pamela McDonnell

Pamela.Mcdonnell@...

212-404-3555

New York University Medical Center and School of Medicine

A big surprise: Young nerve cells can rewind their developmental

clocks

Scientists have identified a gene in the cerebral cortex that

apparently controls the developmental clock of embryonic nerve

cells, a finding that could open another door to tissue replacement

therapy in the central nervous system. In a new study, the

researchers found that they could rewind the clock in young cortical

cells in mice by eliminating a gene called Foxg1. The finding could

potentially form the basis of a new method to push progenitor cells

in the brain to generate a far wider array of tissue than is now

possible.

The study, led by researchers at NYU School of Medicine, is

published in the January 2, 2004 issue of Science magazine.

" What we found was a complete surprise, " says Gordon Fishell, Ph.D.,

Associate Professor in the Department of Cell Biology at New York

University School of Medicine. " No one had believed that it was

possible to push back the birth date of a cortical neuron. There is

this central tenet governing the process of brain development, which

says that late progenitor cells [forerunners of mature cell types]

cannot give rise to cell types produced earlier in development, " he

explains.

" Consequently, while some populations of stem cells exist in the

adult brain, these cells are restricted to producing only a subset

of cell types, " notes Dr. Fishell. " If one's goal is to produce

cells for replacement therapy, some method must be found to turn

back the clock and allow adult stem cells to give rise to the wide

variety of cells made during normal brain development. "

Eseng Lai, Ph.D., of Merck & Co. and one of the study's co-authors,

cloned the Foxg1 gene while he was working at Memorial Sloan-

Kettering Cancer Center in New York. He also did seminal work in the

late 1990s showing that when the gene is eliminated in embryonic

mice, the brain's cerebral hemispheres barely develop. Subsequent

work demonstrated that the gene played a role in the early phases of

cortical development.

The cerebral cortex is massively folded gray matter incorporating

billions of neurons. Despite its complexity, the cortex comprises

six orderly layers of cortical cells that are laid down during

development at a precise time and in a precise sequence. In the

study, the researchers asked which cortical cell types embryonic

mice lacking Foxg1 can generate. Carina Hanashima, Ph.D., a

postdoctoral fellow in Dr. Fishell's laboratory who had previously

worked with Dr. Lai, conducted a series of experiments that made the

analysis possible.

The progenitor cells for the cortex are born in a zone deep in the

brain, and migrate to their assigned layer, depending on the time

they are born. So a cortical cell's identity is based on the date of

its birth. The first cortical cells to be born populate layer 1, the

most superficial layer, which is made up of special Cajal-Retzius

(CR) cells. The next cells born migrate to the innermost layer,

layer 6. Subsequent layers pile up above layer 6 (between layers 6

and 1), and in descending numerical order from 5 to 2. Each layer

has a specific type of neuron associated with it.

The researchers looked at the cortical layers in embryonic mice at a

time in their development when layers 1, 6, and 5, would normally

have already been formed. In mice lacking the Foxg1 gene, the

researchers found that only layer 1, which is made up of CR cells,

was present, and these cells were abundant. The absence of other

cell types implicated the gene in producing later-born cortical cell

types.

One of the ways the scientists were able to identify CR cells was by

the expression of a protein called reelin, which plays a vital role

in building the developing brain and is only present in CR cells.

Mice lacking the protein stumble around so much that they were

named " reelers. " The cortical layers in these mice are scrambled. In

recent years, reelin deficiencies have been linked to such human

disorders as schizophrenia and epilepsy.

In subsequent experiments, the researchers asked how the

overproduction of CR cells occurs. They used a clever biochemical

manipulation that served as a kind of genetic stop watch, allowing

them to temporarily turn off the Foxg1 gene in late progenitor

cells, after the normal birth date of CR cells had passed. In this

way, they observed that cortical cells destined to become layer 5

became CR cells instead. Apparently, the gene orchestrates the

program responsible for ensuring that the cortical layers of the

cerebral cortex are laid down in a precise sequence. When the gene

is inactivated or turned off, the program seems to revert to its

earliest stage.

The researchers do not know how late in the game they can play their

genetic tricks. If they turn off the Foxg1 gene at a later time in

development, such as when cortical layers 2 or 3 are forming, will

progenitor neuronal cells still become CR cells? Are there other

genes that control the developmental clock? If such genes exist, it

may be possible to turn these genes off in adult neural stem cells,

and thereby generate a far broader array of tissue than otherwise

possible. " I would say that the chances of this happening are very

remote, " says Dr. Fishell, " but then again, I never thought that the

clock could have been turned back in neuronal progenitor cells. "

The authors of the study are Gordon Fishell and Carina Hanashima of

NYU School of Medicine; Eseng Lai of Merck; Suzanne Li of Memorial

Sloan-Kettering Cancer Center; and Lijian Shen of Weill Medical

College of Cornell University.

http://www.eurekalert.org/pub_releases/2004-01/nyum-abs122903.php

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