Alternative splicing in axonogenesis

Alternative splicing in axonogenesis

While the neural architecture responsible for the transmission of electrical impulses has been known for more than a century, the basic biology behind how a neuron acquires its one and only axon -- a fundamental component of how neurons communicate -- remains a mystery.

In a new paper, a researcher describe the genetic switches that ignite axon formation. Their work focuses on two molecular components -- polypyrimidine tract binding protein 2 (PTBP2) and the shootin gene (SHTN1).

Previous studies have identified more than 150 genes that play some roles in axon function. The team was surprised to find the overall expression levels of these genes stay relatively flat as the axon grows. If these genes do not change their abundance, how then do they dictate neurons to produce axons?

These genes do change their "character" through a gene regulatory process called alternative splicing. Alternative splicing allows a single gene to produce multiple similar protein isoforms with different functions or identities. According to the senior author, it is as if these genes are transformed to shoulder a new task -- in this case generating an axon.

PTBP2, a specialized RNA binding protein, was about to take center stage in the study. The team found PTBP2 spiked in immature neuron cells. This protein orchestrates the precise choreography behind those splicing events by acting like a switchboard controlling every step of the process that produces the one, essential axon.

Cortical depletion of PTBP2 prematurely induces axonogenesis-associated splicing, causes imbalanced expression of axonogenesis-associated isoforms, and specifically affects axon formation in vitro andin vivo

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 the neural circuit.

"PTBP2 and SHTN1 give us an entry point to understand how splicing changes occur to promote axon growth," the senior author said. "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 this study focused on PTBP2 and the SHTN1 gene, other proteins or genes and their isoforms could also play a role in axon formation. This study was also conducted using mouse neural cells. The team do not know if the same mechanisms will be active in human neural cells. While the study offers a new perspective to this fundamental question, it may be years before these findings could be translated into future therapies.

"Neurodegenerative diseases often manifest through axon degeneration," the senior author said. "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."