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Developmental Biology - Axons

How a neuron grows an axon

Scientists unlock new molecular secrets in a mystery...


While the neural architecture responsible for transmission of electrical impulses has been known for more than a century, the basic biology behind how a neuron makes its one and only axon - the component for how impulses are transmitted - is still a mystery.

In a new paper, research at the University of California, Riverside, describes the genetic switches that ignite axon formation. The work focuses on two molecular components - polypyrimidine tract binding protein 2 (PTBP2) and the shootin gene (SHTN1). The work is published in the February issue of Neuron.
"Neurons are distinct from other cells in the body. They are the only cells that can grow a protrusion (the axon) that can become hundreds and thousands of times longer than the cell body itself."

Sika Zheng PhD, Assistant Professor, Biomedical Sciences School of Medicine, University of California, Riverside, USA.

Neurons transfer information through electrical impulses that travel down the long, threadlike axon extending from the neuron's central body. At the end of the axon, the impulse arcs across a gap to the fingerlike dendrite of a neighboring neuron. This spark - a synapse - conveys information from one neural cell to another. It is a complex circuitry which enables every action, emotion, and thought we experience every day.

"As a field, we typically study one gene to understand a phenomenon, but one gene cannot possibly describe everything that is happening to generate an axon," Zheng explains. "Rather than focusing on one gene, we are thinking globally to explore the process that generates the spectacular set of tasks to create the axon."

Previous studies identified more than 150 genes that play a role in axon function. Zheng and his team were surprised to find the overall expression or function, of these genes remains relatively quiet as an axon grows. That presents a question: if these genes are not increasing in quantity, how do they produce axons?

The genes do change in character through a process called alternative splicing. Alternative splicing allows a single gene to produce multiple similar protein isoforms performing different functions. According to Zheng, they transform to handle the task of generating an axon.
PTBP2, a specialized RNA binding protein, takes center stage in the study. In immature neuron cells, it spikes to orchestrate the precise choreography behind splicing events, acting like a switchboard controlling every step of the process producing that one, essential axon.

At the early stage of axon formation, PTBP2 turns on the long isoform of the SHTN1 gene, which promotes growth of the axon. As the neuron matures, PTBP2 is gradually down regulated and the SHTN1 gene switches from the long isoform to the short isoform. Axon growth stops as the neuron and its axon connect to a neural circuit.

"PTBP2 and SHTN1 give us an entry point to understand how splicing changes occur to promote axon growth," says Zheng. "We can use this information to tease out what is happening at the cellular level, and we are only at the tip of the iceberg."

While the study focused on the PTBP2 and SHTN1 genes, Zheng notes that other proteins or genes and their isoforms could also play a role in axon formation. The study was conducted using mouse neural cells, so the team does not yet know if the exact same mechanisms are active in human neural cells. Zheng cautions it may be years before these findings can be translated into therapies.
"Neurodegenerative diseases often manifest through axon degeneration. We need to think about the splicing process to understand axon degeneration and regeneration for future therapies, but there is a lot more work to be done."

Sika Zheng PhD

Highlights
Axon formation is orchestrated by neural-specific alternative splicing programming
Early axonogenesis-associated splicing changes are governed by PTBP2
Splicing-dependent functional changes of SHTN1 in actin binding and polymerization
PTBP2 depletion impedes axon growth while stimulating axon specification

Summary
How a neuron acquires an axon is a fundamental question. Piecemeal identification of many axonogenesis-related genes has been done, but coordinated regulation is unknown. Through unbiased transcriptome profiling of immature primary cortical neurons during early axon formation, we discovered an association between axonogenesis and neuron-specific alternative splicing. Known axonogenesis genes exhibit little expression alternation but widespread splicing changes. Axonogenesis-associated splicing is governed by RNA binding protein PTBP2, which is enriched in neurons and peaks around axonogenesis in the brain. Cortical depletion of PTBP2 prematurely induces axonogenesis-associated splicing, causes imbalanced expression of axonogenesis-associated isoforms, and specifically affects axon formation in vitro and in vivo. PTBP2-controlled axonogenesis-associated Shtn1 splicing determines SHTN1s capacity to regulate actin interaction, polymerization, and axon growth. Precocious Shtn1 isoform switch contributes to disorganized axon formation of Ptbp2 -/- neurons. We conclude that PTBP2-orchestrated alternative splicing programming is required for robust generation of a single axon in mammals.

Authors
Ming Zhang, Volkan Ergin, Lin Lin, Cheryl Stork, Liang Chen and Sika Zheng.

Acknowledgements
The study was funded by the National Institutes of Health.

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Feb 6, 2018   Fetal Timeline   Maternal Timeline   News  




(A-B) Single neurons with axons (GREEN).
(C-D) Lengths of axon tracts in mouse brains.
Image: Zheng lab, UC Riverside


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