Mixing And Matching Genes To Keep Nerve Cells Straight

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Mixing And Matching Genes To Keep Nerve Cells Straight

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/06/080609124611.htm

With fewer than 30,000 human genes with which to work, Nature has to

mix and match to generate the myriad types of neurons or nerve cells

needed to assemble the brain and nervous system. Keeping this

involved process on the straight and narrow requires a clever balance

of promotion and inhibition, said researchers from Baylor College of

Medicine in Houston in a report that appeared recently in the journal

Developmental Cell.

" Our finding should have implications for the entire stem cell

field, " said Dr. Soo-Kyung Lee, assistant professor of molecular and

cellular biology at BCM. " Scientists are seeking to make particular

cell types using combinations of embryonic genes. They need to

keeping mind that you do not just push them forward down one pathway.

You must also suppress related pathways. "

" During embryonic development, one needs to generate a lot of

different types of neurons, " said Lee, also a faculty member in the

BCM Graduate School of Biomedical Sciences. " How are they being

generated at the right time and place? To assemble the brain, you

need all these different types of neurons. With a limited number of

genes, how do you generate such a complex system? "

" We want to understand the molecular mechanisms that allow one gene

to influence the formation of many neurons, " she said.

They found that both promotion of one pathway and inhibition of

another are required to keep the cells on the right road to cell fate

determination.

" One factor does not determine cell fate, " she said. It's a

combination of factors or genes that together affect neuron formation.

She and her colleagues concentrated their work on the development of

motor neurons in mice. Two types of nerve cells -- spinal motor

neurons and V2-interneurons -- are required for motor coordination.

As they become those cells, they share important regulatory factors,

said Lee.

" They share a cell lineage pathway, " she said. " We asked how do we

generate two different lineages from one pathway? "

A cocktail of the transcription factors Isl1 and Lhx3 can cause

embryonic cells to become motor neurons, she said.

" If we put only Lhx3 into the embryonic neural stem cells, they

become V2-interneurons, " she said. However, deleting the genes can

cause the pathways to converge, resulting in hybrid cells that result

in the death of the embryos.

This does not happen in Nature, she said, and they found that a gene

called Hb9, expressed only in motor neurons, blocks the ability of

Lhx3 to cause embryonic neural stem cells to become the V2-

interneurons.

" Once you turn on the complex of Isl1 and Lhx3, then you also turn on

a repressor that blocks the cells from going down the alternative

pathway to becoming V2-interneurons, " she said. The motor neuron fate

of those cells is sealed. They found a similar repressor function in

the V2-interneuron pathway.

" We think this is a delicately developed system, " said Lee. " We don't

think this mechanism is restricted to motor neurons. "

Others who took part in this work include Seunghee Lee, Bora Lee,

Kaumudi Joshi and Jae W. Lee, all of BCM and L. Pfaff of the

Salk Institute in La Jolla, California.