Vitamin A, retinoic acid and vision

Dr. Shweta Kukreja and Ms. Niveda Udaykumar’s joint interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Work described here is done in the lab of Prof. Jonaki Sen in the department of Biological Sciences & Bioengineering at Indian Institute of Technology, Kanpur. Currently, Dr. Kukreja is Postdoctoral Fellow in the University of Massachusetts Medical School, USA and Ms. Udaykumar is PhD in the department of Biological Sciences & Bioengineering at Indian Institute of Technology, Kanpur. Dr. Kukreja and Ms. Udaykumar jointly published a paper titled “Retinoic acid signaling regulates proliferation and lamina formation in the developing chick optic tectum” as joint first authors in Developmental Biology journal (2020).

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

Our recent study, published in the Developmental Biology journal, provides insight on how the optic tectum in the chick brain develops. The optic tectum is a multilayered structure in the brain that receives visual information from the eye. Here visual information is integrated and transferred to higher visual centers to bring about appropriate responses. Since birds rely heavily on visual cues for their survival, this structure is very well developed and is one of the most prominent structures in the chicken brain. Several signaling molecules have been implicated in controlling the development of the optic tectum. Our study has shown that one such molecule derived from Vitamin A, known as retinoic acid (RA), is crucial for the proper development of the optic tectum.

There are several reports in the literature which show that RA signaling regulates many aspects of nervous system development. Yet, prior to our study, its involvement in the development of the optic tectum had remained unexplored. The experiments in our study were performed in the developing chick embryo. The reasons being that unlike the mammalian embryo which develops inside the mother’s body, the chick embryo develops in the egg, making it accessible to experimental manipulation from the earliest stage. Further, fertilized chicken eggs are easily procured in large numbers, and thus it is a more cost-effective model system as compared to the mouse.

. The presence of different levels of RA signaling from anterior to posterior tectum.

In a previous study, we had observed that an enzyme responsible for producing the active form of RA is localized to certain regions within the optic tectum in the chick embryo. Moreover, the enzyme responsible for destroying the active form of RA is localized in the complementary areas of the optic tectum. This suggested that RA signaling may not be uniformly distributed throughout the optic tectum. Indeed on further exploration, we found differential levels of RA signaling present in the optic tectum from the anterior to the posterior (Figure 1). To determine the role of RA signaling in this context, we turned off RA signaling during the development of the chick optic tectum. We found that this manipulation increased cell proliferation, and paradoxically led to a decrease in thickness of the tectal wall. We speculate that this could be due to the role of RA in regulating the proliferation-differentiation balance in the developing optic tecum. In other words, in the absence of RA the progenitor cells continue to proliferate while less production of neurons occurs, leading to the reduced thickness of the tectal wall. Besides, we also found that RA regulates the migration of a subset of tectal neurons. After they are produced, the tectal neurons migrate in three waves to settle down in the appropriate layer. We found that the neurons that belong to a late migratory wave failed to migrate and reach their destination layer in the absence of RA signaling (Figure 2).

: The effects upon inhibition of RA signaling in the optic tectum.

“[…] first time demonstrated that RA signaling is involved in the development of the chick optic tectum and its importance for proper layer formation or lamination of the tectal wall.”

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

We have for the first time demonstrated that RA signaling is involved in the development of the chick optic tectum and its importance for proper layer formation or lamination of the tectal wall. Through our study, the well-documented role of RA signaling in the maintenance of the proliferation-differentiation balance is strengthened further. The regulation of cell proliferation and tectal neuron migration at precise time windows suggests a multi-faceted role of RA signaling within the same tissue.

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

We would say that we had two eureka moments during this study. The first one was when we found that blocking RA signaling affected the lamination of the tectal wall, since certain layers of the tectum were found to be missing on performing anti-MAP2 immunostaining. MAP2 is a protein present in the alternate plexiform layers of the tectum. This was one of the first pieces of data that we had obtained, leaving us extremely delighted. The second moment was when we found that RA signaling blockade increases cell proliferation. The manipulation leads to an almost two-fold change in the number of cells per unit area which was quite unexpected for us.

What do you hope to do next?

In this study, we have demonstrated that RA signaling regulates cell proliferation and migration of the tectal neurons, but how it does so, remains to be explored. Hence, we next wish to explore the mechanistic details of these processes so that we can find the molecules that function downstream of RA to regulate these processes. This will lead to the discovery of additional players that are involved in the development of the optic tectum. This will also add to the overall understanding of how the critical phenomena such as cell proliferation, differentiation and migration are controlled in the brain during its development.

Where do you seek scientific inspiration?

As we work with the developing chick embryo, in some experiments, the effect of the manipulation is immediate and fascinating. What is more intriguing is that these changes occur in real-time during the development of the embryo. We would say that we draw our inspiration from the phrase “Seeing is believing!”.

How do you intend to help Indian science improve?

India reports a high occurrence of neurodevelopmental disorders in children, especially in the age group of 2–9 years. Yet, till date, the exact etiology of these disorders is poorly understood. As a team of developmental neurobiologists, our group aims to identify some of the underlying molecular players involved in these disorders. We hope that our research in this area will provide insights and help us to understand their complex mechanisms. The goal is to lower the incidence rates of these disorders in children in India. Further, therapeutics and diagnostics procedures may be designed to improve the health of children globally.

Reference

Kukreja S#, Udaykumar N#, Yogesh B & Sen J. Retinoic acid signaling regulates proliferation and lamina formation in the developing chick optic tectum. Developmental Biology 2020, 467, 95–107. #Equal contribution.

Check lab website for more details about ongoing projects: http://sblab.iitk.ac.in/.

Originally published at http://biopatrika.com on October 23, 2020.

Bio- Biology; Patrika: Magazine. An integrated platform for “Vigyan patrika”, “Margdarshak”, “BioKonnect” and “Jobs”. Indian Science highlights.

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