Mythological stories around the world have mentions of evil multi-headed monsters. Be it the Raavana of the Ramayana, or the Cerberus of the Greek Underworld. But as the saying goes, reality is indeed stranger than fiction. Meet the planarians -- small flatworms belonging to the phylum Platyhelminthes which are found in fresh and salt-water bodies all over the world. What truly sets them apart is their amazing ability to regenerate body parts – cut them into as many pieces as you like, and you have that many planarians.
In fact, early experiments by T.H Morgan, an American evolutionary biologist, geneticist, embryologist, have shown that if an individual Planaria were to be cut into 273 pieces, each piece could give rise to a new individual!
“Planarians have become an attractive model to study regeneration because of their robust capacity to regenerate the whole body from a tiny fragment”, remarks Dr. Praveen Vemula of the Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore. “The regeneration process in this animal is driven by the pluripotent stem cells known as neoblasts, which are functionally equivalent to embryonic stem cells. They also have well-organized tissue and organ systems such as the brain, eye, branched intestine, protonephridia (equal to kidneys), muscle and epidermis”, he explains detailing why it is so fascinating to study planarians.
Now, this fascination has resulted in a team of researchers from Dr. Dasaradhi Palakodeti’s lab and Dr. Praveen Vemula’s lab using planarians to explore the process of how the brain is regenerated in these organisms. Studies in the past have shown that that expression of various genes is important for neurogenesis. But the genes involved in this process are yet to be understood. In their recent study published in the journal Development, teams led by Dr. Vemula and Dr. Palakodeti have explored the role of microRNAs (miRNAs) in neurogenesis. The team also developed a novel delivery method to introduce genetic materials into the flatworms.
“The messenger RNA (mRNA) carries the decoded genetic information from DNA, to synthesize specific proteins in the cell through a process called translation. These proteins then carry out specific functions. MicroRNAs (miRNAs) are small, non-coding RNA fragments containing typically 21-22 nucleotides, which bind to mRNA and prevent protein synthesis either through degrading mRNA or by inhibiting the translation process. Therefore, miRNAs can fine-tune protein levels inside the cell, and thus, regulate the cellular functions”, explains Dr. Palakodeti.
While it was known that miRNAs play a big role in our cells, this study has shown the particular effect a family of miRNAs, namely microRNA-124 (miR-124), have in the regeneration of the brain and visual system in planarians. Through various experiments, including the creation of “knockdown” planarians which lacked a certain gene, the team could show that inhibiting the action of the miR-124 in individuals lead to various deformities like small eyes, abnormally large distance between eyes or complete loss of eyes, and a reduction in the overall brain size.
From previous studies, it is known that the planarian brain is made up of different types of cells. In this study, the researchers could show that of the three major subtypes of cells examined, two of them (gad+ and th+) dramatically decreased and there was a significant increase in the other type (chat+) in the absence of miRNA-124. Through further experiments, they proved that miRNA-124 was primarily required for specification of neural subtypes and organization of the brain during planarian regeneration. The researchers were also able to prove that the role of the miRNA in eye generation was independent of brain regeneration.
Conducting experiments to derive these results required the scientists to introduce genetic material into the Planarians. The methods normally used to carry out such experiments fell short of the requirements of this study. To overcome this challenge the researchers designed a novel vehicle, a cationic, non-viral liposomal vector to deliver miRNAs into the Planarian body. “Thus far, people were focusing on only lipid/liposomal structures and completely ignored the nature of the cell. For the first time, we took another approach. First, we understood the nature of cell membrane and later based on the information we gained, we have developed custom designed liposomes which led to the delivery of nucleic acids into Planaria which was not possible before. We are also using this approach to deliver transgenes, which is not possible currently in the planarian field.” adds Dr. Vemula explaining the need for a novel delivery method.
But what implications do understanding brain regeneration in a small flatworm have on larger mammals? “Several studies have shown that most of the pathways critical for neoblast function were also conserved in the mammalian stem cells, which makes planarian stem cells an ideal model to study stem cell biology. Therefore, planarian model can be efficiently used to identify pathways that regulate neuronal organization and patterning, which could have implications in understanding the neurodevelopmental disorders in mammalians”, signs off Dr. Palakodeti.