Synapse is the site of defect in majority of neurodevelopmental disorders. As a part of CBDR, the primary goal of my lab is to study the contribution of synaptic protein synthesis to neurodevelopmental disorders. The ability to regulate protein synthesis in response to physiological stimulus in spatio-temporally controlled manner is a major contributor to the functional autonomy of synapses. We aim to identify the key players of this process and elucidate their function at synapse. In this effort we focus on ‘RNA centric regulation of translation’ mediated by microRNAs and other non-coding RNAs coordinated by specific set of RNA binding proteins. One such RNA binding protein we are studying is Fragile X Mental Retardation Protein (FMRP), the absence of which causes fragile X syndrome (FXS).

Fragile X syndrome is the most common inherited cause of intellectual deficiency resulting from the trinucleotide expansion and subsequent silencing of FMR1 gene. Dysregulated synaptic protein synthesis is proposed to be the cause of fragile X syndrome. We are studying the function of FMRP at two stages, 1) during the differentiation of pluripotent embryonic stem cells to neuronal precursors and to mature neurons 2) integrating the synaptic signaling to regulate protein synthesis in mature neurons. We have identified that FMRP regulate multiple aspects of translation, starting from ribosome biogenesis, mRNA transport to synaptic protein synthesis. In mature neurons we are particularly interested in identifying the composition of FMRP containing miRSC (microRNA induced silencing complex) which enables FMRP to act act as a molecular switch in response to multiple signaling pathways.

As part of CBDR we are collaborating with Prof. Sumantra Chattarji to study the role of FMRP in amygdala and with Prof. Siddharthan Chandran to study the role of FMRP during neuronal differentiation using embryonic stem cell (ESCs) and induced pluripotent stem cell (iPSCs) models. The mechanistic insight derived from our studies on FXS will be extended to other autism spectrum disorders.