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.”
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.
This work was supported by grants from the National Institutes of Health.
About the Salk Institute for Biological Studies
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes, and cardiovascular disorders by studying neuroscience, genetics, cell and plant biology, and related disciplines.
Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.
Gina Kirchweger | Newswise Science News
Further reports about: > Biological Studies > Cortex > Emx1 > FGF10 > Functional Airspace Blocks > Genetics > Lhx2 > Stem cell innovation > cerebral > cerebral cortex > epithelial cells > genetic mechanism > methanol fuel cells > neurodegenerative disorder > progenitor cells > spinal cord > stem cells > transcription factor
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Materials Sciences