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An embryonic mouse forebrain shows the genetically modified neurons in the neocortex (orange/yellow). Cortical stem cells and neurons in other brain regions remain unaltered. Image Credit:Andreas Zembrzycki, Salk Institute for Biological Studies

Brain cells are capable of switching "careers"

Scientists at the Salk Institute have found a single molecule controls the fate of mature sensory neurons. This discovery changes our view of neurons – which are responsible for specific tasks in the brain – as being much more flexible than anticipated.

By studying sensory neurons in mice, Salk researchers found that malfunction of a single molecule can prompt a neuron to make a switch — changing from originally being destined to process sound to instead processing vision.

The finding, reported May 11, 2015 in PNAS, will help neuroscientists better understand how brain architecture is molecularly encoded and how it can become miswired. It may also point to ways to prevent or treat human disorders (such as autism) that feature substantial brain structure abnormalities.

“We found an unexpected mechanism that provides surprising brain plasticity in maturing sensory neurons.”

Andreas Zembrzycki PhD, study’s first author and senior research associate at the Salk Institute.

The mechanism is a transcription factor called Lhx2 that can be used to switch genes on or off to change the function of a sensory neuron in mice.

It was known that Lhx2 is present in many cell types and is needed by a developing fetus to build body parts. Without Lhx2, animals typically die in utero. However, it was not well known that Lhx2 also affects cells after birth.

“This process happens when the neuron matures and no longer divides. We did not understand before this study that relatively mature neurons could be reprogrammed in this way,” says senior author Dennis O’Leary, Salk professor and holder of the Vincent J. Coates Chair in Molecular Neurobiology. “This finding opens up a new understanding about how brain architecture is established and a potential therapeutic approach to altering that blueprint.”

Scientists at the Salk Institute also discovered new details into how certain master proteins dictate neuron specialties. This new work could help them better understand, and perhaps ultimately prevent or treat, diseases like Rett syndrome, schizophrenia and autism. It had been believed that programming neurons was a one-step process — that stem cells which generated neurons also programmed their functions once they matured. But the Salk team found another step, that Lhx2 transcription factor in mature neurons ultimately controls neuronal fate.

In the study, scientists manipulated Lhx2 to make the switch in neuronal fate shortly after birth (when mouse neurons are fully formed and considered mature). They observed controlling Lhx2 let them instruct neurons situated in one sensory area to process a different sense, enlarging one region at the expense of another. However, scientists don’t know yet if targeting Lhx2 will allow neurons to change their function throughout an organism’s entire life.

O’Leary: “This study provides proof that the brain is very plastic and that it responds to both genetic and epigenetic influences well after birth. Clinical applications for brain disorders are a long way away, but we now have a new way to think about them.”

“Since this study was conducted in mice, we don’t know the time frame in which Lhx2 would be operating in humans, but we know that post-birth, neurons in a baby’s brain still have not settled into their final position–they are still being wired up. That could take years,” Zembrzycki adds.

However, the findings may be an ingredient that contributes to the success of early intervention in some very young children diagnosed with autism, adds Zembrzycki.

“The brain’s wiring is determined genetically as well as influenced epigenetically by environmental influences and early intervention preventing brain miswiring may be an example of converging genetic and epigenetic mechanisms that are controlled by Lhx2.”

Andreas Zembrzycki PhD, senior research associate, the Salk Institute.

Significance
The mammalian neocortex is divided into specialized modality-specific areas that are responsible for the processing of sensory information. This architecture is critical, because altered area size affects normal sensory function and behavior in animals and humans. Current knowledge suggests that sensory area specification is dominated by patterning genes expressed in cortical progenitors. We show that postmitotic deletion of the transcription factor LIM homeobox 2 (Lhx2) in cortical neurons does not affect area patterning in progenitors but strongly alters sensory areas, demonstrating that specification of area identity in progenitors alone is insufficient. We suggest a novel and more comprehensive model of cortical area patterning that incorporates these revelations and define the relevance of postmitotic mechanisms in determining the functional properties of cortical areas.

Abstract
Current knowledge suggests that cortical sensory area identity is controlled by transcription factors (TFs) that specify area features in progenitor cells and subsequently their progeny in a one-step process. However, how neurons acquire and maintain these features is unclear. We have used conditional inactivation restricted to postmitotic cortical neurons in mice to investigate the role of the TF LIM homeobox 2 (Lhx2) in this process and report that in conditional mutant cortices area patterning is normal in progenitors but strongly affected in cortical plate (CP) neurons. We show that Lhx2 controls neocortical area patterning by regulating downstream genetic and epigenetic regulators that drive the acquisition of molecular properties in CP neurons. Our results question a strict hierarchy in which progenitors dominate area identity, suggesting a novel and more comprehensive two-step model of area patterning: In progenitors, patterning TFs prespecify sensory area blueprints. Sequentially, sustained function of alignment TFs, including Lhx2, is essential to maintain and to translate the blueprints into functional sensory area properties in cortical neurons postmitotically. Our results reemphasize critical roles for Lhx2 that acts as one of the terminal selector genes in controlling principal properties of neurons.

Authors of the work are Andreas Zembrzycki, Carlos G. Perez-Garcia, and Dennis D. M. O’Leary, all of the Salk Institute for Biological Studies; and Chia-Fang Wang and Shen-Ju Chou, of the Institute of Cellular and Organismic Biology, Academia Sinica, in Taiwan.

The work was funded by the National Institutes of Health and a grant from the National Science Council, Taiwan.

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 probes 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 infectious diseases 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, MD, the Institute is an independent nonprofit organization and architectural landmark.

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