Biology subjects

Muzumdar, S.

Publications and source records attributed to Muzumdar, S..

4 recordsLinked to original sources

bioRxiv2026

Genetic and stochastic basis of phenotypic discordance in 16p11.2 mouse model deletion

Recurrent copy number variations such as the 16p11.2 deletion (del/+) represent a significant genetic risk for neurodevelopmental disorders, showing incomplete penetrance and variable expressivity. Here we describe a striking discordance in a genetic mouse model of human 16p11.2 deletion. Using electrocorticography experiments, we detected that approximately 50% of the isogenic del/+ mice exhibited increased susceptibility to seizures from low doses of the convulsant drug pentylenetetrazole (PTZ). Some of these mice also displayed spontaneous epileptiform brain activity. Next, we used two-photon microscopy tomography (STPT) with c-Fos-GFP (c-Fos+) as a reporter of neuronal activity to obtain images of the entire mouse brain. We examined del/+ mice that exhibited low or high responses to PTZ. Low responders exhibited minimal c-Fos+ activation. However, they had activating circuits that suggest the presence of compensatory mechanisms that suppress seizures. These circuits include the reticular nucleus of the thalamus, the pretectal region, the pedunculopontine nucleus, and the superior colliculus. In contrast, high-responder mice exhibited high c-Fos+ expression, corresponding to a fast seizure phenotype. Using whole-brain imaging, we analyzed brain volume and detected significant differences in the cortex between low- responder and high-responder del/+ mice. In the group with higher seizure susceptibility, we observed a notable decrease in cortical volume with significant differences in several brain regions compared to low responders. Additionally, some high-responder mice showed null expansion areas compared to low-responder mice. During the longitudinal behavioral analysis, the high-responder group of mice exhibited more severe sleep disturbances and an increase in repetitive grooming. Finally, to identify transcriptional correlates of the low- versus high- response phenotypes in adulthood, we performed bulk RNA-seq on somatosensory cortex punches from adult del/+ mice stratified by seizure response. Seizure-prone del/+ mice exhibited reduced activity-dependent immediate early gene signatures and coordinated changes in regulatory programs, including decreased expression of transcriptional regulators and metabotropic glutamate receptor genes, compared to low responders. Together, these findings define two distinct adult del/+ subgroups with convergent circuit, structural, behavioral, and molecular signatures.

neuroscience↗

bioRxiv2025

The plant circadian clock exerts stronger control over the diel proteome than the transcriptome

AbstractThe plant circadian clock is a genetic circuit composed of multiple mutually-regulating transcription factors that together synchronize internal biological rhythms to the [~]24-hour period of planetary rotation. While it has been known for over a decade that nearly 40% of the transcriptome in the model plant Arabidopsis oscillates with a circadian rhythm, it is yet unclear to what extent this translates to the proteome. Here, through parallel quantitative proteome and transcriptome time-course profiling of Arabidopsis wild-type plants and a panel of clock deficient plant lines, we show that specific clock genes exercise extensive control over diel proteome rhythmicity, and to a much greater extent than they do the transcriptome. This control results in a clock-dependent synchronization of rhythmic proteins along a bimodal phase distribution that is lost in circadian clock deficient plants. This suggests pervasive post-translational control of gene expression by specific elements of the circadian system, notably the morning expressed LHY/CCA1 module. Our findings imply that the circadian clock exercises much greater control of gene expression through proteostasis mechanisms than previously recognised, necessitating a recalibration of our current understanding of clock proteins as primarily transcriptional regulators.

plant biology↗

bioRxiv2024

Tracing Endometriosis: Coupling deeply phenotyped, single-cell based Endometrial Differences and AI for disease pathology and prediction

Endometriosis, affecting 1 in 9 women, presents treatment and diagnostic challenges. To address these issues, we generated the biggest single-cell atlas of endometrial tissue to date, comprising 466,371 cells from 35 endometriosis and 25 non-endometriosis patients without exogenous hormonal treatment. Detailed analysis reveals significant gene expression changes and altered receptor-ligand interactions present in the endometrium of endometriosis patients, including increased inflammation, adhesion, proliferation, cell survival, and angiogenesis in various cell types. These alterations may enhance endometriosis lesion formation and offer novel therapeutic targets. Using ScaiVision, we developed neural network models predicting endometriosis of varying disease severity (median AUC = 0.83), including an 11-gene signature-based model (median AUC = 0.83) for hypothesis-generation without external validation. In conclusion, our findings illuminate numerous pathway and ligand-receptor changes in the endometrium of endometriosis patients, offering insights into pathophysiology, targets for novel treatments, and diagnostic models for enhanced outcomes in endometriosis management.

molecular biology↗

bioRxiv2022

Conserved cell-type specific signature of resilience to Alzheimer's disease nominates role for excitatory cortical neurons

Alzheimers disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to "cognitive resilience" to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nucleus transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid load. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GRIA3, KCNMA1, and STXBP1. This putative cell type has been implicated in resilience in previous studies on bulk RNA-seq tissue, but our single-nucleus and cross-species approach identifies particular resilience-associated gene signatures in these cells. These novel resilience candidate genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Based on these gene signatures, we identified several potential mechanisms of resilience, including regulation of synaptic plasticity, axonal and dendritic development, and neurite vesicle transport along microtubules that are potentially targetable by available therapeutics. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

neuroscience↗