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Developmental biology - Brain Development

Fetal Brain Subplate Disappears!

Scientists solve the case of the missing fetal brain subplate...

The disappearance of an entire brain region should be cause for concern. Yet, for decades scientists have calmly maintained that one brain area, the subplate, simply vanishes during the course of human development. Recently, however, research reveals genetic similarities between cells in the subplate and neurons implicated in autism - leading a team of Rockefeller scientists to investigate the question: what if subplate cells don't actually vanish at all?

In a new paper, which appears in Cell Stem Cell, Ali H. Brivanlou, the Robert and Harriet Heilbrunn Professor, along with postdoctoral associate Zeeshan Ozair, demonstrate that subplate neurons survive to become part of the adult cerebral cortex a brain area involved in complex cognitive functions. The team goes further to outline a connection between subplate neurons and specific brain disorders, and suggests a strategy for treating such disorders via innovative stem cell techniques.

A happier fate

In the developing brain, the subplate sits below the cortical plate, a precursor to the brain's cortex. During some stages of development, the subplate is the largest layer of the brain making its ultimate disappearance all the more confusing.
"The understanding about the subplate was that it expands and then the cells of the subplate just die out. But we hypothesized: What if these subplate cells are not dying? What if they're just moving to a different level of the cortex becoming part of the cortex?"

Ali H. Brivanlou PhD, Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY, USA.

Brivanlou and his colleagues found ample support for this idea. In samples of brain tissue from various developmental stages, they detected PRDM8, a protein expressed in migrating neurons to help cells move into the cortical plate. They also detected PRDM8 in subplate-like neurons they generated from stem cells. Subsequent experiments showed these laboratory-grown subplate neurons wander away from their original location. All of their findings pointed not to cell death, but to cell movement.
Far from dieing, the subplate seems to nurture development of functional and diverse cells.

Ozair and Brivanlou saw that subplate neurons mature into various types of deep projection neurons cells found in our deepest brain layers.

Cerebral Cortex

The subplate's subplot

In other experiments, the researchers modulated the levels of WNT, a signal pathway known to guide many developmental processes, finding the amount of WNT signaling determined the fate of subplate neurons:

Low levels of WNT yielded projection neurons that extend within the cortex.
High levels of WNT yielded neurons projecting into other brain areas.

These findings have significant implications for understanding brain disorders as projection neuron abnormalities have been linked to several neuro-developmental conditions, including autism. Brivanlou and Ozair's research suggests these abnormalities manifest very early in fetal development.

Ozair explains: "A lot of the genes associated with autism are first expressed in the subplate. If subplate neurons don't die but instead become part of the cortex, they will carry those mutations with them."

In addition to shedding light on the early stages of brain disorders, the research presents new hope for preventing or treating such disorders through stem-cell therapy. Brivanlou and Ozair hope one day their findings will make it possible to treat neurodegenerative disease using such techniques to generate scarce neuronal cells from subplate-like stem cells.
"The deep layers of the cortex are involved in many diseases: Alzheimer's, Lou Gehrig's, and Huntington's disease, which all kill off specific types of deep-projection neurons. When we think about cellular-replacement therapy, we need to think about how these cells are made in the first place."

M. Zeeshan Ozair PhD, Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY, USA.

Brivanlou adds: "This research shows us how to generate these neurons directly, because we now know the signaling mechanism necessary for their fate to be unveiled."

Subplate neurons (SPNs) in vitro can generate cortex deep projection neurons (DPNs)
SPNs in fetal cortex express multiple markers of DPNs and enter the cortical plate
WNT signaling regulates post-mitotic projection neuron identity of SPNs
SPNs in the caudal cortex are the only cells enriched in corticofugal neuron genes

Cortical deep projection neurons (DPNs) are implicated in neurodevelopmental disorders. Although recent findings emphasize post-mitotic programs in projection neuron fate selection, the establishment of primate DPN identity during layer formation is not well understood. The subplate lies underneath the developing cortex and is a post-mitotic compartment that is transiently and disproportionately enlarged in primates in the second trimester. The evolutionary significance of subplate expansion, the molecular identity of its neurons, and its contribution to primate corticogenesis remain open questions. By modeling subplate formation with human pluripotent stem cells (hPSCs), we show that all classes of cortical DPNs can be specified from subplate neurons (SPNs). Post-mitotic WNT signaling regulates DPN class selection, and DPNs in the caudal fetal cortex appear to exclusively derive from SPNs. Our findings indicate that SPNs have evolved in primates as an important source of DPNs that contribute to cortical lamination prior to their known role in circuit formation.

Authors: M. Zeeshan Ozair, Christoph Kirst, Bastiaan L. van den Berg, Albert Ruzo, Tiago Rito, and Ali H. Brivanlou.

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Jun 26, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Human fetal brain layers developing over time.
Image credit: The Rockefeller University, New York, NY.

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