What makes a neuron a neuron?

Researchers finds clues within RNA-binding proteins in brain cells that helps explain why almost every RNA-binding protein has a sibling - or "paralog."

Focusing on the sibling RNA-binding proteins - PTBP1 and PTBP2 in the nervous system — a team of University of Southern California researchers found both induce unique functions when neural stem cells change into neurons. Neuronal cells process and transmit information through the exchange of electrical and chemical signals.

"PTBP1 is expressed in neural stem cells, while PTBP2 is found in differentiating neurons. Their expressions are almost mutually exclusive.

During brain development, cells switch expression from PTBP1 to become PTBP2. This contributes to the neuronal differentiating process, and can offer insights into understanding what makes a neuron a neuron."

Sika Zheng, an assistant professor of biomedical sciences in the School of Medicine at the University of California, Riverside, who led the research project.

The research has implications for fine-tuning stem cell therapy strategies for neurologic disorders such as stroke, ALS, and Parkinson's disease. It appeared Dec. 6 in Cell Reports.

"Understanding at the molecular level how these proteins work and how neurons acquire their building blocks can help us speed up the differentiation process and make it more efficient," Zheng explains, as in humans it normally takes months to differentiate a stem cell into a neuron.

PTBP1 and PTBP2 could be seen as siblings both born to be musicians, except PTBP1 is a master of classical music, while PTBP2 is a master of contemporary music.

"One can imagine that both [siblings] like music and sometimes perform a piece in the same way," Zheng adds. "But at other times they interpret and play the music differently, for example, with different styles and instruments, they give the same score different meanings and emotions. In this analogy, the musical scores are primitive genetic messages or premature RNA in a cell."

Premature RNA is unprocessed RNA — a molecule "copied" from a DNA template within the cell nucleus. Premature RNA undergoes extensive modification with the aid of RNA binding proteins, to produce mature RNA genetic messages. Depending on how that modification is conducted, the same premature RNA can be differently processed and create variations on an RNA genetic message.

"Using the same analogy, performance is the final product of mature RNA,"  says Zheng. "Neural stem cells and neurons have somewhat different collections of RNA thanks to the activity of PTBP1 and PTBP2."

Composition of all the mature RNA in a cell determines that cell's identity.

Abstract Highlights
•PTBP1 partially rescues PTBP2 loss during brain development
•PTBP1 and PTBP2 regulate overlapping but distinct sets of alternative exons in vivo
•Exons exhibit developmental regulation following their sensitivity to PTBP1/2
•Differential targeting is likely determined by cofactors rather than RNA binding

Summary
Families of alternative splicing regulators often contain multiple paralogs presumed to fulfill different functions. Polypyrimidine tract binding proteins PTBP1 and PTBP2 reprogram developmental pre-mRNA splicing in neurons, but how their regulatory networks differ is not understood. To compare their targeting, we generated a knockin allele that conditionally expresses PTBP1. Bred to a Ptbp2 knockout, the transgene allowed us to compare the developmental and molecular phenotypes of mice expressing only PTBP1, only PTBP2, or neither protein in the brain. This knockin Ptbp1 rescued a forebrain-specific, but not a pan-neuronal, Ptbp2 knockout, demonstrating both redundant and distinct roles for the proteins. Many developmentally regulated exons exhibited different sensitivities to PTBP1 and PTBP2. Nevertheless, the two paralogs displayed similar RNA binding across the transcriptome, indicating that their differential targeting does not derive from their RNA interactions, but from possible different cofactor interactions.

Other Authors: Zheng was joined in the research by John K. Vuong, a graduate student, and Min Zhang, a postdoctoral scholar, who work in his lab; Chia-Ho Lin and Douglas Black at UCLA; and Liang Chen at the University of Southern California.

The research was supported by grants from the National Institutes of Health.

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(F ) Co-staining of FLAG-PTBP1 and neuron marker NeuN in the neocortex
(G) Co-staining of FLAG-PTBP1 and neuron marker NeuN in the hippocampus. 
Scale bars, 100 μm.
Image Credit: Vionnie Yu, Zon Lab, Harvard University