Author interview: Mohd Ali Abbas Zaidi completed his Bachelors in Biochemistry (Hons.) and Masters in Biotechnology from Aligarh Muslim University. He further went on to pursue his PhD in the lab of Dr Jonaki Sen, at Department of Biological Sciences and Bioengineering, IIT Kanpur in Developmental Biology. He is currently researching on Lipid metabolism and hepatocellular carcinoma as a Postdoctoral Research Associate in the lab of Dr. Micah B. Schott, at The University of Nebraska Medical Center Omaha, NE, USA.
Sweta Kushwaha is a PhD scholar in the laboratory of Prof. Jonaki Sen in the Department of Biological Sciences and Bioengineering, IIT-Kanpur. She received her Bachelor’s degree in Biology and Master’s degree in Zoology from Chhatrapati Shahu Ji Maharaj University (CSJMU), Kanpur.
Lab: Prof. Jonaki Sen in the Department of Biological Sciences and Bioengineering, IIT-Kanpur.
Research Summary: Telencephalic hemisphere formation is a complex and precisely timed process, which begins in the chick forebrain with an invagination in the middle of the roof plate. However, the factor(s) that determine the position/site of invagination in the roof plate remain to be elucidated. In this study, we have demonstrated that as development proceeds, a region of lower thickness appears in the middle of the roof plate, which marks the position where the invagination begins. Our investigations have implicated an interplay between the canonical (pSMAD 1/5/9 dependent) and the non-canonical (LIMK dependent) arms of BMP signaling in regulating this process. We have demonstrated that LIMK dependent non-canonical BMP signaling induces high levels of phosphorylated Cofilin (pCofilin) in the middle of the roof plate, which in turn alters Actin cytoskeleton dynamics, resulting in this region being thinner than the lateral regions. This study has provided the first mechanistic insight into how forebrain roof plate invagination begins and has thrown light on the role played by BMP signaling in this process.
In our lab we study the development of the nervous system using chick and mouse embryos. We are specifically interested in studying the gene’s interaction networks directing morphogenesis, patterning and neuronal differentiation in the forebrain. Our goal is to elucidate the molecular basis of the above-mentioned phenomena by first identifying the signaling molecules involved followed by identification of the target genes downstream. We are also interested in identifying the interactions between the different signaling pathways involved in these processes. The current study explores the interplay between the canonical and non-canonical arms of the BMP signaling to regulate the morphogenesis of the chick forebrain roof plate, governing the overall development of the adult chick forebrain and sheds more light on the broad topic of holoprosencephaly. — Dr. Jonaki Sen, Indian Institute of Technology Kanpur, India.
What was the core problem you aimed to solve with this research?
The adult forebrain has two cerebral hemispheres which are separated by the midline (longitudinal fissure). This midline (longitudinal fissure) is the outcome of invagination of the roof plate of the early embryonic forebrain vesicle and serves to divide the forebrain vesicle. Each of these forebrain vesicles later in adulthood develops into the cerebral hemisphere. This embryonic forebrain midline invagination does not only serve as a divider of the cerebral hemisphere but also functions to give rise, to as well as correctly position, certain midline-derived structures, such as choroid plexus, cortical hem, and hippocampus. The improper invagination of the roof plate midline results in fused cerebral hemispheres and absent midline-derived structures. This condition is known as holoprosencephaly. Here in this study, we investigated the role of Bone Morphogenetic Protein signaling (BMP signaling) in governing the cell length and the thickness of the forebrain roof plate midline, which further governs how the forebrain roof plate midline will undergo invagination.
How did you go about solving this problem?
We utilized fertilized chicken eggs, which on incubation give rise to the chicken embryo. We took the chicken embryos of different stages and subjected their developing forebrain vesicles to coronal sectioning. Examining these coronal sections, we were able to appreciate that the forebrain roof plate undergoes significant morphological changes and folds into a W shape while invaginating (Fig1). We found a mutually exclusive expression domain of active canonical BMP signaling as well as cytoskeleton modifier phospho-Cofilin (Fig1 L-M). We went ahead to directly manipulate the function of these genes by utilizing the technique of electroporation. This technique enabled us to introduce the plasmid constructs expressing our desired gene, directly into the forebrain roof plate of developing chicken embryos without harming the embryo itself. We found that if anything goes wrong with the fine interplay between BMP signaling and activity of cofilin, it alters the forebrain roof plate morphogenesis, consequently affecting its invagination process.
How would you explain your research outcomes (Key findings) to the non-scientific community?
The proper development of an adult individual is at the mercy of fine interplay between morphogenesis, differentiation and patterning which happens at the embryonic level. If anything goes wrong with any of these delicate processes, it leads to the developmental defects in adult organisms resulting in poor quality of life. Our study provides an example of how disrupted forebrain roof plate morphogenesis can lead to improper brain development.
What are the potential implications of your findings for the field and society? Holoprosencephaly affects 1 in 250 conceptions and its prevalence in live birth is 1:16000. The severity of this disease is defined by extent of brain malformations and is classically divided into alobar, semilobar and lobar forms. The developmental disorders cannot be reversed, but can be prevented by genetic assessment. Our study is an attempt to identify novel genetic key players in the process of forebrain development. Our work advances the basic understanding of the complex signaling interactions that shape the developing brain.
What was the exciting moment during your research?
Most exciting moments during the research were opening incubated chicken eggs to see the miniature form of every organ of an adult organism. Another exciting moment was discovery of an antagonistic relationship between canonical and non-canonical BMP signaling in the chick forebrain roof plate.
Reference: Zaidi MAA#, Kushwaha S#, Udaykumar N, Dethe P, Sachdeva M, Sen J. Interplay of canonical and LIMK mediated non-canonical BMP signaling is essential for regulating differential thickness and invagination during chick forebrain roof plate morphogenesis. Dev Biol. 2025 Jan 15;520:125-134. #Equal contribution.
