How stem cells yield functional regions in 'gray matter'
The cerebral cortex, the largest and most complex component of the brain, is unique to mammals and alone has evolved human specializations. Although at first all stem cells in charge of building the cerebral cortex-the outermost layer of neurons commonly referred to as gray matter-are created equal, soon they irrevocably commit to forming specific cortical regions. But how the stem cells' destiny is determined has remained an open question.
In the Oct. 11 advance online edition of Nature Neuroscience, scientists at the Salk Institute for Biological Studies report that they have identified the first genetic mechanism that determines the regional identity of progenitors tasked with generating the cerebral cortex. Their discovery reveals a critical period during which a LIM homeodomain transcription factor known as Lhx2 decides over the progenitors' regional destiny: Once the window of opportunity closes, their fate is sealed.
"These findings provide a foundation for understanding the important process of developing the distinct regions of the cerebral cortex and determining their unique properties," says Dennis O'Leary, Ph.D., a professor in the Molecular Neurobiology Laboratory, who led the study.
This knowledge will also potentially help in understanding the genetic underpinnings of many neurodegenerative disorders, and provide the means to uniquely specify stem cells to repair specific parts of the brain ravaged by disease or injury.
During embryonic brain development, the stem cells that will give rise to the cerebral cortex pass through a series of tightly regulated stages: from omnipotent stem cells to cortical progenitor cells that will eventually form functionally specialized regions, such as the six-layered neocortex, the biggest and evolutionarily most recent part of the cerebral cortex, and the older three-layered olfactory cortex among others.
Early during neurogenesis, stem cell-like progenitor cells known as neuroepithelial cells undergo symmetric cell division to expand the pool of neuroepithelial cells. Later, they differentiate into more mature progenitor cells referred to as radial glia, which divide asymmetrically to produce a constant stream of both progenitors and neurons, the latter migrating outward to establish the gray matter of specialized cortical regions.
In a study published earlier this year, O'Leary and Setsuko Sahara, Ph.D., a senior research associate in the O'Leary lab, uncovered that the growth factor Fgf10 controls the timing of the critical transition period that bridges the early expansion phase of neuroepithelial cells and the later neurogenic phase of radial glia. Now, the Salk researchers wanted to know when and how these cells acquire their future regional identity.
The predominant model for determining genetic mechanisms that specify the production of distinct types of neurons has been the spinal cord. "In the spinal cord distinct subpopulations of progenitors that generate different classes of neurons are defined by unique sets of transcriptions factors, and are separated by sharp spatial borders," explains O'Leary. "But in the cerebral cortex the situation is very different. There are no genes that we or anybody else have identified that define separate subpopulations of progenitors that generate neurons that form the different regions of the cerebral cortex. Thus a different mechanism must operate."