The defining characteristic of progenitor cells that will go on to form the cerebral cortex is the expression of Emx1, a homeodomain transcription factor. O'Leary proposed that the regional identity of progenitors in the Emx1 lineage may involve a graded expression of one or more transcription factors that define unique subpopulations of progenitors via differences in their expression levels. The most promising candidate was Lhx2, which is expressed in all progenitors of the Emx1 lineage but at different levels in a graded pattern. Testing this hypothesis required that Shen-ju Chou, Ph.D., a senior research associate in the O'Leary lab and first-author of this study, develop a novel genetically-engineered mouse to delete Lhx2 in a conditional fashion.

Shen-ju and two other members of O'Leary's research team, Carlos G. Perez Garcia, Ph.D. and Todd T. Kroll, Ph.D., then used this mouse line to delete Lhx2 at different times during embryonic development to assess whether Lhx2 had any say over the progenitors' fate in producing regions of the cerebral cortex.

When the researchers deleted Lhx2 from neuroepithelial cells before they made the transition into radial glia, the neocortex was transformed into a large, out-of-place olfactory cortex. But when they deleted Lhx2 just one day later the transformation did not occur, indicating that the progenitors' regional identity was fixed.

"These experiments show that Lhx2 regulates the regional fate decision of progenitors of the Emx1 lineage to generate neocortex or olfactory cortex" says Chou. "Lhx2 needs to be present in appropriate quantities during a critical window of time for progenitors to make the appropriate fate decision. Adds O'Leary, "This finding dovetails nicely with our previous study on Fgf10 by demonstrating that the critical time window for the regional fate decision determined by Lhx2 closes once neuroepithelial cells have made the transition to radial glia, a step regulated by Fgf10."

O'Leary's team plans to extend this work to determine the mechanism of action of Lhx2, and whether modulating Lhx2 levels can direct, or restrict, the differentiation of embryonic stem (ES) cells, or induced pluripotent stem (iPS) cells. This work will be important for developing strategies for brain repair.

Source: Salk Institute