Bio Patrika interviews Dr. Kinare and Dr. Iyer on their thoughts about “the role of protein interactions in hippocampus development”

Dr. Veena Kinare and Dr. Archana Iyer’s joint interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Work described here is done in the lab of Prof. Shubha Tole at the Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai. Currently, Dr. Kinare is working as Assistant Manager, Medical Affairs in pharmaceutical company Cipla and Dr. Iyer is DST INSPIRE faculty fellow at TIFR Mumbai. They published a paper titled “An evolutionarily conserved Lhx2-Ldb1 interaction regulates the acquisition of hippocampal cell fate and regional identity” as joint first authors in Development journal (2020).

How would you explain your paper’s key results to the non-scientific community?

The brain is a complex structure that is responsible for a variety of functions we carry out. One specific area of the brain, the hippocampus, is important for learning and memory. How does the hippocampus form? We identified a “molecular toolkit” that is key to the development of the hippocampus.

A variety of proteins act as “molecular tools” inside each cell. Some proteins bind to DNA and control which genes are expressed and, by extension, which new proteins get produced inside cells. Our study uncovers two proteins Lhx2 and Ldb1, which bind to each other in an interesting configuration, like Lego pieces (Fig. 1).

Figure 1. Lhx2 protein (in purple) binds to DNA with its homeodomain (HD) and to its partner, Ldb1(in yellow) with its LIM interacting domain (LID). Two Ldb1 molecules can interact with each other using the dimerisation domain (DD)

This arrangement allows two molecules of Lhx2 to bind to distant fragments of DNA and bring them together via a process called “DNA looping” (Fig. 2).

Figure 2. The combination-protein with the Lhx2 DNA binding domain and the dimerisation domain of Ldb1.

It was already known that the hippocampus is severely shrunken when either one of these partners is missing. In our study, we demonstrate that we can “rescue” this defect by introducing an artificial piece of DNA that produces a “combination-protein” that has the key portions of Lhx2 and Ldb1 (Fig. 3). Thus we prove that the Lhx2-Ldb1 partnership is the functional toolkit for hippocampal development.

Figure 3. Lhx2-Ldb1 interaction can bring distant regions of the DNA closer by looping. The combination-protein consists of key portions of Lhx2 and Ldb1, which would allow for DNA looping.

Interestingly, the interaction between Lhx2 and Ldb1 was first discovered in the fruit fly. This interaction is crucial to make the fly’s wing – without either one of these proteins, the wing is a shrunken stub, but if the “combination-protein” is introduced, the wing is restored. The parallels between the fly wing and the mouse hippocampus bring out how important this partnership between Lhx2 and Ldb1 is because it has been conserved across billions of years of evolution.

“[…] interactions and their downstream effectors can be explored in hippocampal developmental defects.”

What are the possible consequences of these findings for your research area?

The hippocampus is involved in many important functions of the brain; therefore, pinpointing pathways involved in its formation help understand how its complexity is brought about. Additionally, these interactions and their downstream effectors can be explored in hippocampal developmental defects. This could be potentially useful for therapeutic applications.

What was the exciting moment (eureka moment) during your research?

Many of our ideas have developed as a result of stimulating discussions in the lab. The idea of using a “combined” protein composed of Lhx2 and Ldb1, similar to the one used in flies, to rescue hippocampal defects in the brain too originated from one such exciting discussion initiated by a former lab-member Hari Padmanabhan. He prepared the DNA for the “combination-protein” which we used for fly experiments. We were elated when this idea came to fruition. The hippocampus in the mutants, which has lost Ldb1 lacks several hallmarks of the normal hippocampus. It is severely shrunken and does not express region-specific features. We were excited when we could rescue this mutant phenotype and observed hippocampal area-specific markers appear in the regions targeted with the combination construct. 

What do you hope to do next?

Transcription factors act in multi-component complexes. Currently, we have identified one such interaction in the development of the hippocampus. We are now in the process of examining the mechanism by which these two molecules could be carrying out their job. For instance, Lhx2 can be a part of a complex that brings about chromatin looping and thereby interacts with proteins distant from its binding region on the DNA. We would therefore like to examine other such molecules that could be involved in the hippocampal specification. We would also like to explore the chromatin landscape concerning these interactions during development.

Where do you seek scientific inspiration?

Quoting Richard Feynman, “the pleasure of finding things out” is what inspires us. Science has progressed through decades of work done by curious minds to understand the occurrences around us. To be a part of the research community that strives to answer questions in biology that might someday benefit society at large is the driving force behind our work.

How do you intend to help Indian science improve?

We at TIFR, regularly participate in scientific outreach programs aim to promote an understanding of biology at the school level. We have also visited rural schools and presented various scientific concepts in the local language. This, we believe, will enable many students to get a glimpse of real-world research, its significance, and implications in our society, which we hope will encourage them to pursue a career in science.

Reference

Kinare V#, Iyer A#, Padmanabhan H, Godbole G, Khan T, Khatri Z, Maheshwari U, Muralidharan B, Tole S. An evolutionarily conserved Lhx2-Ldb1 interaction regulates the acquisition of hippocampal cell fate and regional identity. Development 147: dev187856 (2020). #Equal contribution

Learn more about Prof. Shubha Tole’s research endeavors here https://www.tifr.res.in/~dbs/faculty/stolelab/Principal_Investigator.html


First author’s current role and research interest

Dr. Veena Kinare
Assistant Manager, Medical Affairs, Cipla, Mumbai
I’m currently working in medical affairs in a pharmaceutical company. Medical affairs form a bridge between the R&D and the commercial side of the organization, which allows me to get a flavour of both sides. In this field, one has to stay abreast of the upcoming drugs and therapeutical approaches and communicate this vital information to stakeholders from diverse backgrounds.
It has been an enriching experience working with doctors, key opinion leaders and marketing and sales teams. Working in medical affairs lets me utilize the skills and training I obtained during my PhD, including literature review, drafting effective
presentations, and communicating accurate, scientific information.

Email: veenakinare@gmail.com


Dr. Archana Iyer
DST INSPIRE faculty fellow, Tata Institute of Fundamental Research, Mumbai
Much like we juggle with various decisions in life, cells in the brain make choices. In particular, I refer to cells responsible for producing neurons and glia which are two of the many cell types that populate the brain. This is an essential process because a mother cell has to make the right amount of neurons and glia for a properly functioning brain. Based on their genetic program and environment, these mother cells decide whether to divide to make daughter cells like themselves or to make daughter cells that are either neurons or glia. And all this is achieved during a specific time period. I am interested in examining these cell fate choices and which molecules are important for this process. Several neurodegenerative diseases, for example, are influenced by the incorrect numbers of neurons and glia. Along with my colleagues in Prof. Tole’s lab and thanks to the Department of Science and Technology for the INSPIRE fellowship, I am exploring some of these molecules relevant to this process as it can uncover many unknown mechanisms of generating these cells in the brain.

Email: archana.n.iyer@gmail.com

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