If you were to function as a cell, what type would you be?

Insight from work on Rudhira
Insight from work on Rudhira

Imagine having the supreme ability of transforming yourself to any other functional being of your choice with impeccable precision, just like Mystic from X-men (Marvel fans would get the hint)! Setting aside Sci-Fi, in fact if we take a look inside us, each of us do have such remarkable cells in our body that carries immense potential (although choice is not conscious) to develop into a variety of structurally and functionally diverse cell types, especially in the early stages of life (embryonic stage) as well as during the growth phase. These gems are called Stem Cells; literally living up to their name – being the stem from which several types of cells branch out. Not just that, these cell types even take up the responsibility of replacing damaged cells in certain body parts of adult organisms. Be it understanding how an entire organism develops from a single cell or exploring its regenerative abilities for treating certain chronic diseases, worldwide research on stem cells has progressed appreciably over the last 40 years.

Prof. Maneesha S. Inamdar’s laboratory at the Molecular Biology and Genetics Unit of JNCASR, carries out fundamental research in stem cell and developmental biology using mouse and Drosophila as the model organisms. One of the long-term ongoing research at her lab is on a gene named ‘Rudhira’ that is fundamental to the formation and functioning of new blood vessels during mouse embryonic stage. The gene Rudhira (meaning blood-red) at first, was found to be expressed in the red blood cell lineage of mouse embryonic stem cells and subsequently has been shown to be conserved between Drosophila, mouse and human! The discovery of this novel gene was quite a turning point since the expressed protein has 98% similarity to a protein from the gene overexpressed in human breast cancer cells (human BCAS3). The later has been shown to have expression even in the embryonic stem cells, most importantly detected to have abnormal expression levels in malignant tumors and blood vessels.

Baseline findings
Further in-depth experiments revealed a vital role of Rudhira in directing movement of cells to particular locations required for the process of wound healing. During development in multicellular organisms, errors during the movement of cells to destined locations often result in serious diseases like formation of tumor or vascular defects. On this axis, Prof. Inamdar’s team established that the gene Rudhira codes for a protein that rearranges and promotes cell division control protein (a protein involved in regulation of cell cycle) during the process of wound healing. Lack of this protein was shown to have severe consequences on cell’s cytoskeletal structure (even though cells are microscopic, they have a skeletal structure too that holds them, aids their movement, plays substantial role in cell division) and orientation that ultimately affect the elemental process through which new blood vessels develop.

Current breakthrough
After establishing and functionally characterizing the role of Rudhira in-vitro, it was then time to replicate the results in-vivo. Ronak Shetty and Divyesh Joshi, two of the current graduate students from Prof. Inamdar’s lab involved in this project, continuing work initiated by former graduate student Dr. Mamta Jain, accomplished in generating the first Rudhira knockout mouse (Knockout literally translates to removal; in genetics it is the process through which an existing gene of interest is inactivated or replaced by an artificial piece of DNA with the aim to study what the gene normally function as).

These images depict normal vascular patterning in the control embryo (left) and irregular and discontinuous vasculature in the Rudhira knockout embryo (right) at day 10.5 of embryonic stage.
These images depict normal vascular patterning in the control embryo (left) and irregular and discontinuous vasculature in the Rudhira knockout embryo (right) at day 10.5 of embryonic stage.

In their recently published paper in Scientific Reports, the team details systematic experiments to show major developmental defects in mouse embryos lacking Rudhira. Rudhira knockout mice embryos were unable to survive beyond 9 days of their embryonic stage and were detected by decline in growth and significantly affected patterning in the dorsal aorta of heart. Through immunostaining and subsequent microscopic structure analysis of relevant tissues, the team was able to show that even if the developmental rate was not affected, severe defects in shape and structure of blood vessels in the head and heart of Rudhira knockout embryos were detected (these embryos had shrunken heart chambers and abrupt dorsal aorta among other structural defects in the development). Expression of this gene was further shown to be crucial for normal structuring and functioning in the inner layers of blood vessels.

Dr. Ronak Shetty (left), Prof. Maneesha S. Inamdar and Divyesh Joshi (right) at Vascular biology Laboratory, MBGU, JNCASR.
Dr. Ronak Shetty (left), Prof. Maneesha S. Inamdar (center) and Divyesh Joshi (right) at Vascular Biology Laboratory, MBGU, JNCASR.

This piece of work led by Prof. Inamdar not only reaffirmed the pivotal role of Rudhira in blood vessel development through in-vitro and in-vivo studies, but has also contributed to the field of developmental biology by establishing a mouse model for future studies in stem cell and medical research in cardiovascular development. For more studies from Vascular Biology Laboratory, click here.

Reference
Shetty, R., Joshi, D., Jain, M., Vasudevan, M., Paul, J.C., Bhat, G., Banerjee, P., Abe, T., Kiyonari, H., VijayRaghavan, K. and Inamdar, M.S., 2018. Rudhira/BCAS3 is essential for mouse development and cardiovascular patterning. Scientific reports, 8(1), p.5632.

The article is authored by Manaswini Sarangi, Evolutionary Biology Laboratory, EIBU, JNCASR.

Cover Art by: Manaswini Sarangi.

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