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One protein impacts 200 others in sperm development

Scientists have found that a single protein called Ptbp2 controls a network of over 200 genes central to how developing sperm in mice move and communicate.

The Ptbp2 protein regulates how RNA is processed throughout sperm formation. Newly developing sperm are constantly chopping and trimming their own genetic material in a process called "splicing" which allows small pieces of RNA to be trimmed into blueprints for new proteins.
By using different trimming patterns or "alternative splicing", sperm cells create multiple protein blueprints from one single gene.

The work is published in Cell Reports

Developing sperm use alternative splicing more than any other of the body's cell types. The procedure produces high levels of RNA fragments inside sperm progenitor cells, or germ cells. Progenitor cells are like stem cells, but have already become more specific than a stem cell on their way to becomming a single cell type. Scientists are not sure how or why germ ( or sex) cells use alternative splicing at such a high rate.

"The importance of RNA splicing in developing sperm has been of longstanding interest," explains Donny Licatalosi PhD, assistant professor in the Center for RNA Science and Therapeutics at Case Western Reserve University (CWRU), School of Medicine. "We've known for decades that more alternatively spliced RNAs are made during germ cell development than most other developing systems. But whether this is the result of a tightly regulated process, or even a biologically meaningful one, is unclear."
Licatalosi's team focused on one protein, Ptbp2, which is always found attached at RNA splicing sites. He hopes understanding RNA splicing in germ cells would help his team better understand mechanisms that go wrong in normal sperm developmental and explain defects.

Licatalosi's team then deleted the gene which codes for Ptbp2 and followed the level and function of alternatively spliced RNAs typically found in four different stages of sperm development.

After collaborating with the CWRU department of Virology, Next Generation Sequencing department, to observe how genetically modified cells interact with normally developed germ cells, Licatalosi's team discovered that without the Ptbp2 protein, alternative splicing went awry for over 200 genes inside developing sperm.

Many of the 200 affected genes code proteins involved in sorting and trafficking other proteins within the germ cell. If impaired, germ cells can't move, transport proteins, or communicate with other cells. Therefore, genetically modified germ cells never develop into normal sperm. Deleting major proteins impacted Sertoli cells creating defects in the cytoskeleton that allows the cell to physically move and interact with germ cells. These results suggest Ptbp2 is central to RNA splicing and somehow controls proper sperm development.

Adds Licatalosi, "Proper tissue development and function depends on highly orchestrated networks of different cell types talking to one another in an ordered and timely manner. Deficits in this process underlie a range of human diseases. Our data, and that from other labs, indicates that regulators of tissue-specific splicing may have critical roles in establishing cell-to-cell networks needed for proper tissue development and functionality."

Alternative splicing is regulated in a stage-specific manner in spermatogenesis
Ptbp2 is a critical regulator of alternative splicing in germ cell development
Ptbp2 controls a network of traffick and cell adhesion genes via exon repression
Germ-Sertoli cell crosstalk requires Ptbp2 expression in germ cells

Alternative splicing has essential roles in development. Remarkably, spermatogenic cells express more alternatively spliced RNAs compared to most whole tissues; however, regulation of these RNAs remains unclear. Here, we characterize the alternative splicing landscape during spermatogenesis and reveal an essential function for the RNA-binding protein Ptbp2 in this highly regulated developmental program. We found that Ptbp2 controls a network of genes involved in cell adhesion, migration, and polarity, suggesting that splicing regulation by Ptbp2 is critical for germ cell communication with Sertoli cells (multifunctional somatic cells necessary for spermatogenesis). Indeed, Ptbp2 ablation in germ cells resulted in disorganization of the filamentous actin (F-actin) cytoskeleton in Sertoli cells, indicating that alternative splicing regulation is necessary for cellular crosstalk during germ cell development. Collectively, the data delineate an alternative splicing regulatory network essential for spermatogenesis, the splicing factor that controls it, and its biological importance in germ-Sertoli communication.

Authors: Molly M. Hannigan, Leah L. Zagore, Donny Licatalosi.

For more information about Case Western Reserve University School of Medicine, please visit: http://case.edu/medicine.

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Mouse sperm.
Image Credit: Kenyon College, Gambier, Ohio

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