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Gene Switch For Cerebral Cortex Growth Discovered

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University of California, Irvine researchers have identified a gene that is specifically responsible for generating the cerebral cortex, a finding that could lead to stem cell therapies to treat brain injuries and diseases such as stroke and Alzheimer’s.

3-D reconstruction of a slice of embryonic cerebral cortex after electroporation of a plasmid allowing expression of a Green Fluorescent Protein in various cortical cell types.

Dr. Edwin Monuki, doctoral student Karla Hirokawa and their colleagues in the departments of Pathology & Laboratory Medicine and Developmental & Cell Biology found that a gene called Lhx2 serves as the long-sought cortical “creator” gene that instructs stem cells in the developing brain to form the cerebral cortex. This portion of the brain is responsible for higher sensory and cognitive functions, such as language, decision-making and vision. Without this gene, cortical cells will not form.

“This new understanding of Lhx2’s role in cortical development can potentially be used in stem cell research efforts to grow new cortical neurons that can replace damaged ones in the brain,” said Monuki, an assistant professor of pathology. “This finding has implications for continuing efforts to help people recover from a stroke or slow the progress of neurodegenerative diseases.”

Lhx2 is among a group of genes — called selector genes — that act during key moments of embryonic and fetal development, directing stem cells to grow into specific parts of the body — such as brain, blood and bone.

In tests on rodents, the researchers found that Lhx2’s cortical selector activity is critical only during the stage when the developing cortex is made up of stem cells, not before or after. In addition, they found that cortical stem cells that don’t express the Lhx2 gene turn into a different cell type — called a hem cell — that induces neighboring cells to become the hippocampus, the oldest part of the cortex in evolutionary terms and a major memory center of the brain.

Lhx2’s role in cerebral cortex development has far-reaching implications in the nascent field of stem cell research. The Monuki lab is currently studying how to activate Lhx2 genes in neural stem cells and initiate the process in which new cortical cells can grow. “If successful, the concept of using Lhx2 to instill stem cells with cortical properties could be a basis of clinical studies that could one day help treat patients,” he said.

Researchers in Monuki’s lab are deeply involved with stem cell research. Last month, they published a study identifying a new way to sort stem cells that should be quicker, easier and more cost-effective than current methods. The technique could in the future expedite therapies for people with conditions ranging from brain and spinal cord damage to Alzheimer’s and Parkinson’s diseases.

Science 18 January 2008: Vol. 319. no. 5861, pp. 304 – 309 DOI: 10.1126/science.1151695
Lhx2 Selector Activity Specifies Cortical Identity and Suppresses Hippocampal Organizer Fate
Vishakha S. Mangale,1* Karla E. Hirokawa,2* Prasad R. V. Satyaki,1* Nandini Gokulchandran,1* Satyadeep Chikbire,1 Lakshmi Subramanian,1 Ashwin S. Shetty,1 Ben Martynoga,1 Jolly Paul,1 Mark V. Mai,3 Yuqing Li,4 Lisa A. Flanagan,5 Shubha Tole,1{dagger} Edwin S. Monuki2,5{dagger}

The earliest step in creating the cerebral cortex is the specification of neuroepithelium to a cortical fate. Using mouse genetic mosaics and timed inactivations, we demonstrated that Lhx2 acts as a classic selector gene and essential intrinsic determinant of cortical identity. Lhx2 selector activity is restricted to an early critical period when stem cells comprise the cortical neuroepithelium, where it acts cell-autonomously to specify cortical identity and suppress alternative fates in a spatially dependent manner. Laterally, Lhx2 null cells adopt antihem identity, whereas medially they become cortical hem cells, which can induce and organize ectopic hippocampal fields. In addition to providing functional evidence for Lhx2 selector activity, these findings show that the cortical hem is a hippocampal organizer.

1 Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
2 Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA.
3 Department of Biology, Swarthmore College, Swarthmore, PA 19081, USA.
4 Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
5 Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: (E.S.M., cKO component); (S.T., ESC chimeras)

Written by huehueteotl

January 19, 2008 at 4:30 pm

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