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Neural stem cells transport proteins just like RNA

Scientists can now observe molecules as they ascend neural stem cells to form new neurons in the brain. Duke University scientists got their first glimpse of these molecules moving along a stem cell highway which exists at the same length as developing neurons.

This new view has given them a piece of unexpected information. That information is that not having enough of the protein FMRP — found in Fragile X syndrome and autism related disorders — affects the movement of molecular cargo up and down stem cells. Their findings appear in the December issue of Current Biology.

"The moving molecules we saw in these stem cells could be crucial to their function — including their decision to become neurons. We are excited about these new discoveries and have many more questions."

Debra Silver PhD, Assistant Professor, Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA, and the study's senior investigator.

Neural stem cells are buried deep within the brain and outwardly project long, thin extensions. Their end tips — called "endfeet" — reach as far as the uppermost layer of the brain and prevent neurons from migrating any further.

Compared to the main body of the stem cell, far-flung endfeet live in a vastly different environment of the brain. That environment may ultimately influence whether a neural stem cell generates another stem cell or becomes a neuron.

Neural stem cells are so long, researchers think they might even be acting like neurons, shipping molecules over their long length. Including, perhaps, transporting messenger RNA (mRNA) molecules needed to manufacture proteins.

After extensive adjustments, postdoctoral researcher Louis-Jan Pilaz was able to create a frame-by-frame video of mRNAs moving down neural stem cell shafts.

The video suggests neural stem cells are highways for molecular transport, carrying not just mRNAs but also many other types of proteins.

When mRNA reaches the stem cell endfeet it gets translated into protein by cell machinery. Silver's group was able to show this with a new test the lab group developed allowing them to isolate endfeet from the rest of the cell.

Using fluorescent tags, graduate student Ashley Lennox was able to capture how new proteins were being made within the endfeet.

The team knew mRNA is moved in a controlled fashion to endfeet, not merely diffused. But which molecules controlled this step? Examining a handful of molecules known to influence RNA, they were surpised to find the Fragile X syndrome protein — FMRP — bound and carried the mRNAs.

A few previous studies by other groups had implicated FMRP in neural stem cell function, but very little was known about its role in brain development.

The group found 115 different mRNAs that FMRP latch onto.

Almost 30 percent of these are linked to brain diseases. Almost half of those are enhanced in autism. The team followed one of the mRNAs and using a mouse model of Fragile X, demonstrated how that mRNA needed FMRP to arrive at the neural stem cell's endfeet.

Silver's group is now studying how production of proteins are controlled within endfeet, and what protein changes in neural stem cells are occurring over the course of brain development. They are also separating FMRP's different functions to gauge how each affects brain development.

Abstract Highlights
•The radial glia basal process is a highway for active directed transport of RNA
•mRNA is locally translated in radial glia endfeet hundreds of micrometers from the soma
•Endfeet FMRP-bound RNAs encode autism-related signaling and cytoskeletal regulators
•FMRP controls RNA localization and active mRNA transport in radial glia

In the developing brain, neurons are produced from neural stem cells termed radial glia [ 1, 2 ]. Radial glial progenitors span the neuroepithelium, extending long basal processes to form endfeet hundreds of micrometers away from the soma. Basal structures influence neuronal migration, tissue integrity, and proliferation [ 3–7 ]. Yet, despite the significance of these distal structures, their cell biology remains poorly characterized, impeding our understanding of how basal processes and endfeet influence neurogenesis. Here we use live imaging of embryonic brain tissue to visualize, for the first time, rapid mRNA transport in radial glia, revealing that the basal process is a highway for directed molecular transport. RNA- and mRNA-binding proteins, including the syndromic autism protein FMRP, move in basal processes at velocities consistent with microtubule-based transport, accumulating in endfeet. We develop an ex vivo tissue preparation to mechanically isolate radial glia endfeet from the soma, and we use photoconvertible proteins to demonstrate that mRNA is locally translated. Using RNA immunoprecipitation and microarray analyses of endfeet, we discover FMRP-bound transcripts, which encode signaling and cytoskeletal regulators, including many implicated in autism and neurogenesis. We show FMRP controls transport and localization of one target, Kif26a. These discoveries reveal a rich, regulated local transcriptome in radial glia, far from the soma, and establish a tractable mammalian model for studying mRNA transport and local translation in vivo. We conclude that cytoskeletal and signaling events at endfeet may be controlled through translation of specific mRNAs transported from the soma, exposing new mechanistic layers within stem cells of the developing brain.

radial glia, corticogenesis, RNA localization, embryonic brain, neural stem cell, FMRP, neurogenesis, local translation, RNA immunoprecipitation, live imaging

The research was supported by Fay/Frank Seed grant from the Brain Research Foundation.

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Dec 13, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Neural stem cells (NSCs) are self-renewing, multipotent and generate neurons and glia cells
for the nervous system. This diagram identifies two stages of neural stem cell transport:
1) RNA proteins being transported up the inside of the Neural Stem Cell (NSC).
2) At the brain barrier, proteins are outwardly projected as long, thin extensions. These "endfeet"
reach as far as the uppermost layer of the brain and prevent neurons from migrating any further.
Image Credit: Debra Silver Lab, Duke University School of Medicine



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