Biology subjects

Chatterjee, M.

Publications and source records attributed to Chatterjee, M..

27 records · Page 2Linked to original sources

bioRxiv2022

Dentate gyrus morphogenesis is regulated by β-CATENIN function in hem-derived fimbrial glia.

The dentate gyrus, a gateway for input to the hippocampal formation, arises from progenitors in the medial telencephalic neuroepithelium adjacent to the cortical hem. Dentate progenitors navigate a complex migratory path guided by two cell populations that arise from the hem, the fimbrial glia, and Cajal-Retzius (CR) cells. Since the hem expresses multiple Wnt genes, we examined whether {beta}-CATENIN, which mediates canonical Wnt signaling and also participates in cell adhesion, is necessary for the development of hem-derived lineages. We report that the fimbrial glial scaffold is disorganized and CR cells are mispositioned upon hem-specific disruption of {beta}-CATENIN. Consequently, the dentate migratory stream is severely affected, and the dentate gyrus fails to form. Using selective Cre drivers, we further determined that {beta}-CATENIN function is required in the fimbrial glial scaffold, but not in the CR cells, for guiding the dentate migration. Our findings highlight a primary requirement for {beta}-CATENIN for the organization of the fimbrial scaffold and a secondary role for this factor in dentate gyrus morphogenesis.

neuroscience↗

bioRxiv2021

Telomere-Dependent Interleukin-1 Receptor Activation Promotes Immune Suppression in Triple-Negative-Breast Cancer

Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (Telomeric Repeat binding Factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8 and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.

cancer biology↗

bioRxiv2021

The glycosylated extracellular domain of MUC1 protects against SARS-CoV-2 infection at the respiratory surface

Mucins play an essential role in protecting the respiratory tract against microbial infections but can also serve as binding sites for bacterial and viral adhesins. The heavily O-glycosylated gel-forming mucins MUC5AC and MUC5B eliminate pathogens by mucociliary clearance while transmembrane mucins MUC1, MUC4, and MUC16 can restrict microbial invasion at the apical surface of the epithelium. In this study, we determined the impact of host mucins and mucin glycans on SARS-CoV-2 epithelial entry. Human lung epithelial Calu-3 cells express the SARS-CoV-2 entry receptor ACE2 and high levels of glycosylated MUC1, but not MUC4 and MUC16, on their cell surface. The O-glycan-specific mucinase StcE specifically removed the glycosylated part of the MUC1 extracellular domain while leaving the underlying SEA domain and cytoplasmic tail intact. StcE treatment of Calu-3 cells significantly enhanced infection with SARS-CoV-2 pseudovirus and authentic virus, while removal of sialic acid and fucose from the epithelial surface did not impact viral entry. Both MUC1 and MUC16 are expressed on the surface of human air-liquid interface (ALI) differentiated airway organoids and StcE treatment led to mucin removal and increased levels of SARS-CoV-2 entry and replication. On the surface of Calu-3 cells, the transmembrane mucin MUC1 and ACE2 are often co-expressed and StcE treatment results in enhanced binding of purified spike protein and SARS-CoV-2 pseudovirus. This study points at an important role for glycosylated mucin domains as components of the host defense that can restrict SARS-CoV-2 infection. Author summarySARS-CoV-2, the virus that has caused the devastating COVID-19 pandemic, causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A fundamental understanding of host factors influencing viral entry is critical to elucidate SARS-CoV-2-host interactions and identify novel therapeutic targets. In this study, we investigated the role of host mucins and mucin glycans on SARS-CoV-2 entry into the airway epithelial cells. Mucins are a family of high molecular weight O-glycosylated proteins that play an essential role in protecting the respiratory tract against viral and bacterial infections. The gel-forming mucins MUC5AC and MUC5B clear pathogens by mucociliary clearance while transmembrane mucins MUC1, MUC4, and MUC16 can restrict or facilitate microbial invasion at the apical surface of the epithelium. The mucin-selective protease StcE specifically cleaves the glycosylated extracellular part of the mucins without perturbing the underlying domains. We show that removal of mucins from the surface of Calu-3 cells and primary airway epithelial cultures with StcE mucinase increases binding of the SARS-CoV-2 spike protein to the respiratory surface and greatly enhances infection. This study demonstrates the important role of glycosylated extracellular mucin domains as a host defense mechanism during SARS-CoV-2 entry. Future efforts should be focused on characterizing the role of specific soluble and transmembrane mucins during the different stages of SARS-CoV-2 infection.

microbiology↗

bioRxiv2021

Human Satellite III long non-coding RNA imparts survival benefits to cancer cells

Long non-coding RNAs are heterogeneous group of transcripts that lack coding potential and have crucial roles in gene regulations. Recent days have seen an increasing association of non-coding RNAs with human diseases, especially cancers. Satellite III (SatIII) lncRNAs are transcribed from pericentromeric heterochromatic region of the human chromosome. Though transcriptionally silent in normal conditions, SatIII is actively transcribed under condition of stress, mainly heat shock. SatII repeat, another component of pericentromeric region of human chromosome, has been associated with wide variety of epithelial cancer. Overexpression of Satellite RNAs induces breast cancer in mice. Though much is known about Satellite RNAs, which includes alpha satellites and SatII repeats, however little is known about SatIII in human cancers. Hence we directed our study to understand the role of human Satellite III repeats in cancerous conditions. In the present study, we show that colon and breast cancer cells transcribe SatIII independent of heat shock, in an HSF1-independent manner. Our study also reveals that, overexpression of SatIII RNA favours cancer cell survival by overriding chemo drug-induced cell death. Knockdown of SatIII sensitizes cells towards chemotherapeutic drugs. SatIII transcript knockdown restores the expression of p53 protein, which in turn facilitates cell death. Heat shock however helps SatIII to continue with its pro-cell survival function. Our results, therefore suggest SatIII to be an important regulator of human cancers. Induction of SatIII is not only a response to the oncogenic stress but also facilitates cancer progression by a distinct pathway that is different from heat stress pathway.

cancer biology↗

bioRxiv2020

Canonical Wnt signaling exerts bidirectional control on choroid plexus epithelial development

The choroid plexus (ChP) secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the ChP epithelium (ChPe) arises from the Wnt-expressing cortical hem. Embryonic mouse and human ChPe both express nuclear {beta}-CATENIN, a canonical Wnt signaling pathway effector, indicating that this pathway is active during ChPe development. Point mutations in human {beta}-CATENIN result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of ChPe identity and an apparent transformation of the ChPe to a neuronal identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell (hESC)-derived organoids. The ChPe is also disrupted when {beta}-Catenin is conditionally inactivated in the mouse. Together, our results indicate that canonical Wnt signaling is required in a precise and regulated manner for normal ChPe development in the mammalian brain.

developmental biology↗

bioRxiv2020

Inhibition of Striatal-Enriched Protein Tyrosine Phosphatase (STEP) Activity Reverses Behavioral Deficits in a Rodent Model of Autism.

Autism spectrum disorders (ASDs) are highly prevalent childhood illnesses characterized by impairments in communication, social behavior, and repetitive behaviors. Studies have found aberrant synaptic plasticity and neuronal connectivity during the early stages of brain development and have suggested that these contribute to an increased risk for ASD. STEP is a protein tyrosine phosphatase that regulates synaptic plasticity and is implicated in several cognitive disorders. Here we test the hypothesis that STEP may contribute to some of the aberrant behaviors present in the VPA-induced mouse model of ASD. In utero VPA exposure of pregnant dams results in autistic-like behavior in the pups, which is associated with a significant increase in the STEP expression in the prefrontal cortex. The elevated STEP protein levels are correlated with increased dephosphorylation of STEP substrates GluN2B, Pyk2 and ERK, suggesting upregulated STEP activity. Moreover, pharmacological inhibition of STEP rescues the sociability, repetitive and abnormal anxiety phenotypes commonly associated with ASD. These data suggest that STEP may play a role in the VPA model of ASD and STEP inhibition may have a potential therapeutic benefit in this model.

neuroscience↗

bioRxiv2020

STEP inhibition prevents Aβ mediated damage in dendritic complexity and spine density in Alzheimers disease.

Loss of dendritic spines and decline of cognitive function are hallmarks of patients with Alzheimers disease (AD). Previous studies have shown that AD pathophysiology involves increased expression of a central nervous system-enriched protein tyrosine phosphatase called STEP (STriatal-Enriched protein tyrosine Phosphatase). STEP opposes the development of synaptic strengthening by dephosphorylating substrates, including GluN2B, Pyk2 and ERK1/2. Genetic reduction of STEP as well as pharmacological inhibition of STEP improves cognitive function and hippocampal memory in the 3xTg AD mouse model. Here, we show that the improved cognitive function is accompanied by an increase in synaptic connectivity in cell cultures as well as in the triple transgenic AD mouse model, further highlighting the potential of STEP inhibitors as a therapeutic agent.

neuroscience↗

bioRxiv2020

Reduced expression of PD-L1 and IDO1 characterises early response to antimonial therapy in cutaneous leishmaniasis patients.

Cutaneous leishmaniasis (CL) is a chronic skin disease caused by Leishmania parasites and in Sri Lanka, CL is caused by L. donovani. Pentavalent antimonials (e.g. sodium stibogluconate; SSG) are first line drugs for CL, despite protracted and painful treatment regimens. Data from animal models indicate that the effectiveness of SSG requires drug-immune synergy, but mechanistic insight from patients is lacking. We studied whole blood and lesion transcriptomes from CL patients in Sri Lanka at presentation and during SSG treatment. In lesions, we identified differential expression of immune-related genes, including immune checkpoint molecules, after the onset of treatment whereas no differentially expressed genes were identified in whole blood. We confirmed reduced lesional PD-L1 and IDO1 protein expression on treatment in a second validation cohort, using digital spatial profiling and quantitative immunohistochemistry. Dual IHC-FISH revealed significantly higher expression of these immune checkpoint molecules on parasite-infected compared to non-infected lesional CD68+ monocytes / macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure and occurred in parallel with a reduction in parasite load. A multivariate cox proportional hazard model showed that patients with lower PD-L1 expression on treatment were more likely to cure earlier (HR= 4.88). Our data support a model whereby the initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition of T cell immunity, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as an early predictor of clinical response to SSG treatment and support the use of PD-L1 inhibition as adjunct host directed therapy in Sri Lankan CL.

immunology↗

bioRxiv2018

Female genetic contributions to sperm competition in Drosophila melanogaster

In many species, sperm can remain viable in the reproductive tract of a female well beyond the typical interval to remating. This creates an opportunity for sperm from different males to compete for oocyte fertilization inside the females reproductive tract. In Drosophila melanogaster, sperm morphology and seminal fluid content affect male success in sperm competition. On the other hand, although genome-wide association studies (GWAS) have demonstrated that female genotype plays a role in sperm competition outcome as well, the biochemical, sensory and physiological processes by which females detect and selectively use sperm from different males remain elusive.\n\nHere, we functionally tested 27 candidate genes implicated via a GWAS for their contribution to the females role in sperm competition, measured as changes in the relative success of the first male to mate (P1). Of these 27 candidates, we identified eight genes that affect P1 when knocked down in females, and also showed that six of them do so when knocked down in the female nervous system. Two genes in particular, Rim and caup, lowered P1 when knocked down in sensory pickpocket (ppk)+ neurons and octopaminergic Tdc2+ neurons, respectively. These results establish a functional role for the females nervous system in the process of sperm competition and expand our understanding of the genetic, neuronal and mechanistic basis of female responses to multiple matings. We propose that through their nervous system, females actively assess male compatibility based on courtship or ejaculates and modulate sperm competition outcome accordingly.

genetics↗