Projects

Project 1: Investigating the alteration of Choroid plexus-CSF system in neurodevelopmental disorders.

Funding: ICMR DHR SRG

Background: The choroid plexus, a brain structure responsible for cerebrospinal fluid secretion, plays a critical role in regulating brain function. Recent studies have linked choroid plexus dysfunction to various neurodevelopmental disorders, including autism spectrum disorder (ASD), hydrocephalus, and Coffin-Siris syndrome. Notably, increased choroid plexus volume has been observed in ASD patients, and many ASD risk genes are highly enriched in this region. However, the mechanistic involvement of the choroid plexus in ASD remains poorly understood.

Objective: Our research focuses on understanding how choroid plexus functionality is altered in mouse models of ASD. Specifically, we aim to explore whether choroid plexus fate specification, maturation, and functionality are disrupted in ASD. To address this, we will employ a multi-omic approach combined with advanced fluorescence live imaging to comprehensively analyze these processes.

Project 2: Investigating cellular and molecular defects in hippocampal development in the maternal high fat diet mouse model.

Funding: CSIR OLP

Background: Fetal brain development is shaped by various internal and external factors during pregnancy. Maternal nutrition, stress, infections, and environmental toxins are among the key elements that influence optimal neural growth. Maternal diet, particularly a high-fat diet (HFD), is a significant environmental factor associated with abnormalities in fetal brain development and functionality. With modern lifestyle changes, HFD consumption has become increasingly common, often exceeding recommended fat intake levels. Maternal HFD has been associated with an increased risk of neurodevelopmental and neurodegenerative disorders in offspring. Human cohort studies report memory deficits and reduced IQ in children born to mothers who consumed a high-fat diet during pregnancy. However, the precise mechanisms by which maternal HFD disrupts the developmental choreography of the hippocampus, the learning and memory center of the brain, remain poorly understood.

Objective: Our study aims to explore how maternal HFD influences hippocampal development, focusing on critical processes such as hippocampal cell fate specification, progenitor proliferation, and synapse formation. Specifically, we seek to investigate how the fundamental steps of hippocampal development are altered spatially and temporally due to maternal HFD. To address this, we will utilize confocal imaging coupled with cell-type-specific markers, RNA sequencing, and proteomics using a HFD mouse model as our experimental system.

Project 3: Investigating the temporal dynamics of Wnt/β-catenin signalling in rhombic lip lineages and its implications on cerebellar development and medulloblastoma. 

Background: The cerebellum is essential for motor coordination, balance, and motor learning, and its development relies on tightly regulated progenitor domains. The rhombic lip (RL) is a key germinal zone that generates cerebellar granule cells, unipolar brush cells (UBCs), and contributes to the hindbrain choroid plexus. Canonical Wnt/β-Catenin signaling is active in the RL and is linked to medulloblastoma. However role of Wnt/β-Catenin signaling in normal lineage development remains unclear. This project investigates how altered Wnt signaling dynamics influence RL-derived cell fate and cerebellar morphogenesis using genetic models of pathway overactivation and suppression.

Objective: First, we will investigate the temporal patterns of Wnt signaling activity in the developing rhombic lip in both mouse and human systems. Second, we aim to examine the consequences of Wnt pathway overactivation and underactivation within the rhombic lip, and determine how these perturbations affect the generation of rhombic lip–derived lineages and overall cerebellar development. Finally, we will establish a cerebellar organoid model to study the temporal regulation of Wnt signaling in a human-relevant system, enabling mechanistic investigation of how changes in signaling dynamics influence cerebellar development. 

Project 4: Investigating the consequences of high-risk ASD mutations using  brain region-specific organoid model.

Background
Although multiple signaling pathways have been implicated in driving the phenotypes associated with Autism Spectrum Disorder (ASD), several fundamental aspects of their regulation and functional consequences remain poorly understood. The physiological outcomes of signaling events depend on multiple regulatory layers, including (1) the spatiotemporal dynamics of receptor–ligand interactions, (2) differential interactions with transcriptional activators or repressors, (3) chromatin accessibility, and (4) interactions with nucleosome-remodeling complexes and histone modifiers. How ASD-associated genetic variants influence these regulatory mechanisms during neurodevelopment remains largely unresolved. 

Objective
In this project, we will investigate region-specific brain organoids (cortical and hippocampal) derived from induced pluripotent stem cell (iPSC) lines harboring mutations in high-confidence ASD-associated genes, including CREBBP, ARID1B, and TRIO. Neuroimaging studies of individuals carrying mutations in these genes frequently report recurrent structural abnormalities in specific brain regions, including the cerebral cortex, hippocampus, cerebellum, and corpus callosum. These observations suggest that disruptions in these genes may converge on key developmental pathways that regulate the formation and maturation of distinct brain regions. Building on these findings, we aim to determine whether these genes regulate shared or distinct molecular and cellular mechanisms underlying regional brain defects, with the broader goal of identifying common and potentially targetable pathways involved in ASD pathogenesis.