Biology subjects

Bhambri, A.

Publications and source records attributed to Bhambri, A..

5 recordsLinked to original sources

bioRxiv2026

Oligodendrocyte ER-phagy Restricts Excessive Myelination by Degrading Sphingolipid Synthases

Myelination is critical for nervous system function. Numerous signaling pathways have been identified that promote myelin sheath growth, disruption of which can lead to hypomyelination, characterized by a reduction in myelin sheath thickness. However, the negative regulators of myelin sheath expansion remain poorly defined. Here, we identify a cellular brake on central nervous system myelination that restricts myelin sheath thickness during brain development. This brake is mediated by a selective form of autophagy, known as endoplasmic reticulum (ER)-phagy, which degrades the ER and its resident sphingolipid synthases. ER-phagy is highly active in oligodendrocytes during myelin membrane expansion, and its impairment leads to ER accumulation, elevated sphingolipid production, and excessive myelin thickening. Genetic reduction of de novo sphingolipid biosynthesis in the ER rescues the hypermyelination phenotype caused by ER-phagy disruption. In summary, our findings establish ER-phagy as a key regulator of sphingolipid metabolism and reveal a mechanistic link between ER homeostasis and myelin production by oligodendrocytes, providing insight into mechanisms underlying pathological hypermyelination.

neuroscience↗

bioRxiv2024

Genetically Labeled Premyelinating Oligodendrocytes: Bridging Oligodendrogenesis and Neuronal Activity

To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs). PreOLs are thought to survey and begin ensheathing nearby axons, and their maturation is often stalled at human demyelinating lesions. Lack of genetic tools to visualize and manipulate preOLs has left this critical differentiation stage woefully understudied. Here, we generated a knock-in mouse line that specifically labels preOLs across the central nervous system. Genetically labeled preOLs exhibit distinct morphology, unique transcriptomic and electrophysiological features, and do not overlap with OPCs. PreOL lineage tracing revealed that subsets of them undergo prolonged maturation and that different brain regions initiate oligodendrogenesis with the spatiotemporal specificity. Lastly, by fate mapping preOLs under sensory deprivation, we find that neuronal activity functions within a narrow time window of preOL maturation to promote their survival and successful integration. Our work provides a new tool to probe this critical cell stage during axon ensheathment, allowing for fine dissection of axon-oligodendrocyte interactions.

neuroscience↗

bioRxiv2023

Autophagy collaborates with apoptosis pathways to control myelination specificity and function

Oligodendrocytes are the sole myelin producing cells in the central nervous system. Oligodendrocyte numbers are tightly controlled across diverse brain regions to match local axon type and number, but the underlying mechanisms and functional significance remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under canonical settings, elicits premyelinating oligodendrocyte apoptosis during development and regulates critical aspects of nerve pulse propagation. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy acts in the TFEB-Bax/Bak pathway and elevates PUMA mRNA levels to trigger premyelinating oligodendrocyte apoptosis cell-autonomously. Autophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath numbers and fine-tune nerve pulse propagation. Our results provide in vivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrocyte number. HIGHLIGHTSO_LIAutophagy flux increases in the premyelinating and myelinating oligodendrocytes C_LIO_LIAutophagy promotes premyelinating oligodendrocyte (pre-OL) apoptosis to control myelination location and timing C_LIO_LIAutophagy acts in the TFEB-PUMA-Bax/Bak pathway and elevates PUMA mRNA levels to determine pre-OL fate C_LIO_LIAutophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath thickness and finetune nerve pulse propagation C_LI

neuroscience↗

bioRxiv2021

Early life trauma leads to violent behavior and its inheritance by impairing local thyroid hormone availability in brain

Escalated and inappropriate levels of aggressive behavior referred to as pathological in psychiatry can lead to violent outcomes with detrimental impact on health and society. Early life trauma triggers adulthood violence and criminality, though molecular mechanisms remain elusive. Here, we provide prefrontal cortex and hypothalamus specific transcriptome profiles of peripubertal stress (PPS) exposed Balb/c adult male mice exhibiting escalated aggression and adult female mice resilient to such aberrant behavioral responses. We identify transthyretin (TTR) as a key regulator of PPS induced escalated aggression and its intergenerational inheritance. TTR mediated long-term perturbation in hypothalamic thyroid hormone (TH) availability contributed to male aggressive behavior without affecting circulating hormone. Ttr gene ablation in hypothalamus impaired local TH signaling including levels of TH transporters (Mct8, Oatp1c1), deiodinase 2(DIO2) and TH responsive genes (Nrgn, Trh and Hr). Escalated aggressive behavior and impaired TTR-TH signaling was also inherited in F1 male progenies. Further, we deciphered Ttr promoter hyper methylation in hypothalamus of such abnormally aggressive males across generations. Interestingly prefrontal cortex showed opposite pattern of Ttr expression as well as long term epigenetic changes. Also, T4 increase by levothyroxine in PFC did not produce any behavioral changes. Our findings reveal that trauma during puberty trigger lasting escalated aggression by epigenetic programming of TTR and consequent impaired thyroid availability in brain. TTR-TH signaling in brain can serve as potential target in reversal of escalated aggression and related psychopathologies.

neuroscience↗

bioRxiv2017

Insights into regeneration from the genome, transcriptome and metagenome analysis of Eisenia fetida

Earthworms show a wide spectrum of regenerative potential with certain species like Eisenia fetida capable of regenerating more than two-thirds of their body while other closely related species, such as Paranais litoralis seem to have lost this ability. Earthworms belong to the phylum annelida, in which the genomes of the marine oligochaete Capitella telata, and the freshwater leech Helobdella robusta have been sequenced and studied. The terrestrial annelids, in spite of their ecological relevance and unique biochemical repertoire, are represented by a single rough genome draft of Eisenia fetida (North American isolate), which suggested that extensive duplications have led to a large number of HOX genes in this annelid. Herein, we report the draft genome sequence of Eisenia fetida (Indian isolate), a terrestrial redworm widely used for vermicomposting assembled using short reads and mate-pair reads. An in-depth analysis of the miRNome of the worm, showed that many miRNA gene families have also undergone extensive duplications. Genes for several important proteins such as sialidases and neurotrophins were identified by RNA sequencing of tissue samples. We also used de novo assembled RNA-Seq data to identify genes that are differentially expressed during regeneration, both in the newly regenerating cells and in the adjacent tissue. Sox4, a master regulator of TGF-beta induced epithelial-mesenchymal transition was induced in the newly regenerated tissue. The regeneration of the ventral nerve cord was also accompanied by the induction of nerve growth factor and neurofilament genes. The metagenome of the worm, characterized using 16S rRNA sequencing, revealed the identity of several bacterial species that reside in the nephridia of the worm. Comparison of the bodywall and cocoon metagenomes showed exclusion of hereditary symbionts in the regenerated tissue. In summary, we present extensive genome, transcriptome and metagenome data to establish the transcriptome and metagenome dynamics during regeneration.

genomics↗