Biology subjects

Na, D.

Publications and source records attributed to Na, D..

10 recordsLinked to original sources

bioRxiv2026

Transferrin participates in the pathogenesis of endometriosis by influencing the proliferation, migration and apoptosis of endometrial cells

Ferroptosis is linked to various diseases, but the role of transferrin (TF) in endometriosis (EM) remains unclear. Expression levels of ferroptosis-related proteins, including transferrin (TF), transferrin receptor (TFRC), and glutathione peroxidase 4 (GPX4), were analyzed by western blotting. Compared to normal endometrial stromal cells, eutopic and ectopic endometrial stromal cells from EM patients exhibited significantly enhanced proliferative and migratory abilities, accompanied by a marked reduction in glutathione (GSH) levels in both eutopic and ectopic tissues. TF and TFRC expression was upregulated in ectopic endometrium relative to normal controls, while GPX4 expression was downregulated. To evaluate the functional role of TF, siRNA-mediated knockdown was performed in endometrial stromal cells, with knockdown efficiency confirmed by western blotting. Functional assays demonstrated that TF knockdown not only suppressed cell proliferation (CCK-8 and clonogenic assays) and migration (wound healing assay) but also significantly increased apoptosis rate (flow cytometry with Annexin V-FITC/PI staining).These findings implicate TF in the pathogenesis and progression of endometriosis, likely through modulating endometrial stromal cell proliferation, migration, and apoptosis.

cell biology↗

bioRxiv2025

Identification of a Thermogenic Target in the Dorsal Raphe Nucleus for Weight Management

Obesity emerges from a complex interplay of factors, including imbalanced interoception, genetic predisposition, and environmental cues, ultimately disrupting body weight homeostasis1. While much research has concentrated on strategies to suppress appetite for sustained weight loss, insufficient attention has been given to counterregulatory mechanisms that promote energy expenditure. Here, we show that chronic inhibition of GABAergic neurons in the Dorsal Raphe Nucleus (DRNVGAT) reduces body weight in diet-induced obese (DIO) mice. In this study, molecular profiling and in-situ hybridization in rodent and human brains revealed that the constitutively activated orphan receptor GPR6 is selectively enriched in DRNVGAT neurons. We next developed and administered a potent and highly selective GPR6 inverse agonist, which significantly reduced weight gain in DIO mice by stimulating brown adipose tissue thermogenesis without affecting appetite. Altogether, this study transitions from transcriptomic profiling, high-throughput drug screening and metabolic phenotyping to successfully identify a novel candidate to treat obesity.

neuroscience↗

bioRxiv2024

Early exposure to Western diet exacerbates visual outcomes in female mice.

Obesity, a growing pandemic in Western societies, significantly impacts metabolic health and contributes to visual disorders. While the systemic consequences of obesity, such as chronic inflammation and insulin resistance, are well-studied in adults, its early-life effects on retinal health remain underexplored. Using a maternal Western Diet (WD) exposure model, we investigated the developmental impact of early-life metabolic disturbances on retinal and cognitive function. Our findings reveal that WD exposure from gestation to early adulthood accelerates the onset of features resembling diabetic retinopathy, including increased retinal vascularization, inflammation, and compromised blood-retina barrier integrity, observed within just four months. Females exhibited heightened vulnerability, showing pronounced ocular defects such as anophthalmia, microphthalmia, and congenital cataracts. These results underscore a critical developmental window during which metabolic disruptions predispose to sex-specific retinal and neurovascular pathologies. This work bridges the link between pediatric and adult obesity, highlighting the urgent need for early interventions to mitigate long-term visual impairments that could further impair recognition memory.

physiology↗

bioRxiv2023

The Role of Terminal Uridyl Transferases in the Circadian Rhythm

The 3 terminal oligo-uridylation, a post-transcriptional mRNA modification, is conserved among eukaryotes and drives mRNA degradation, thereby affecting several key biological processes such as animal development and viral infection. Our TAIL-seq experiment of mouse liver mRNA collected from six zeitgeber times reveals transcripts with rhythmic poly(A) tail lengths and demonstrates that overall 3 terminal uridylation frequencies at mRNA poly(A) tail very-ends undergo rhythmic change. Consistently, major terminal uridylyl transferases, TUT4 and TUT7, have cycling protein expression in mouse liver corresponding to 3 terminal uridylation rhythms, indicating that the cycling expression of TUTases correlates with the rhythmic pattern of uridylation. Furthermore, the double knockdown of TUT4 and TUT7 in U2OS cells lengthens the circadian period and decreases the rhythmic amplitude of clock gene expression. Our work thoroughly profiles the dynamic changes in poly(A) tail lengths and terminal modifications and uncovers uridylation as a post-transcriptional modulator in the mammalian circadian clock.

molecular biology↗

bioRxiv2022

The spindle orienting machinery requires activation, not just localization

The orientation of the mitotic spindle at metaphase determines the placement of the daughter cells. Spindle orientation in animals typically relies on an evolutionarily conserved biological machine comprised of at least four proteins - called Partner of Inscuteable (Pins), Gi, Mushroom body defective (Mud), and Dynein in flies - that exert a pulling force on astral microtubules and reels the spindle into alignment. The canonical model for spindle orientation holds that the direction of pulling is determined by asymmetric placement of this machinery at the cell cortex. In most cell types, this placement is thought to be mediated by Pins, and a substantial body of literature is therefore devoted to identifying polarized cues that govern localized cortical enrichment of Pins. In Drosophila neuroblasts, for example, this cue is thought to be Inscuteable, which helps recruit Pins to the apical cell surface. In this study we revisit the canonical model. We find that spindle orientation in the follicular epithelium requires not only Pins localization but also activation, which relies on direct interaction between Pins and the multifunctional protein Discs large. This mechanism is distinct from the one mediated by Inscuteable, which we find also has an activating step. Together our results show that the canonical model is incomplete. Local enrichment of Pins is not sufficient to determine spindle orientation; an activation step is also necessary.

cell biology↗

bioRxiv2022

Single cell RNA sequencing analysis of mouse cochlear supporting cell transcriptomes with activated ERBB2 receptor, a candidate mediator of hearing restoration mechanisms.

Hearing loss caused by the death of cochlear hair cells might be restored through regeneration from supporting cells via dedifferentiation and proliferation, as observed in birds. We recently found that in mice, activation of ERBB2 in supporting cells promoted the differentiation of hair cell-like cells. Here we analyze transcriptomes of neonatal mouse cochlear supporting cells with activated ERBB2 using single-cell RNA sequencing. ERBB2 induction in vivo generated a new population of cells expressing de novo SIBLING (small integrin-binding ligand n-linked glycoproteins) proteins and their regulators, particularly Secreted Phosphoprotein 1 (SPP1). In other systems, SIBLINGs promote cell survival, proliferation, and differentiation. ERBB2 signaling induced after noise exposure in young adult mice also up-regulated both SPP1 protein and the SPP1 receptor CD44, and drove formation of proliferating stem-like cell aggregates in the organ of Corti. Our results suggest that ectopic activation of ERBB2 signaling in cochlear supporting cells alters the microenvironment, promoting proliferation and cell rearrangements. Together these results suggest a novel mechanism for inducing stem cell-like activity in the adult mammalian cochlea.

neuroscience↗

bioRxiv2020

TRIBE editing reveals specific mRNA targets of eIF4E-BP in Drosophila and in mammals

4E-BP (eIF4E-BP) represses translation initiation by binding to the 5cap-binding protein eIF4E and inhibiting its activity. Although 4E-BP has been shown to be important in growth control, stress response, cancer, neuronal activity and mammalian circadian rhythms, it is not understood how it preferentially represses a subset of mRNAs. We successfully used hyperTRIBE (Targets of RNA-binding proteins identified by editing) to identify in vivo 4E-BP mRNA targets in both Drosophila and mammals under conditions known to activate 4E-BP. The protein associates with specific mRNAs, and ribosome profiling data show that mTOR inhibition changes the translational efficiency of 4E-BP TRIBE targets compared to non-targets. In both systems, these targets have specific motifs and are enriched in translation-related pathways, which correlate well with the known activity of 4E-BP and suggest that it modulates the binding specificity of eIF4E and contributes to mTOR translational specificity.

molecular biology↗

bioRxiv2019

Partial Hearing Restoration after ERBB2 Induction in Deafened Adult Mice

Noise-induced hearing loss (NIHL) affects over ten million adults in the United States, and has no biological treatment. We hypothesized that activation of signaling from ERBB2 receptors in cochlear supporting cells could mitigate cochlear damage. We adopted a new timeline for assessing mitigation that parallels hearing recovery from damage in avians. We drove expression of a constitutively active variant of ERBB2 (CA-ERBB2) in cochlear supporting cells three days after permanent noise damage in young adult mice. Between 100-200 supporting cells in the apical cochlea expressed a lineage marker, indicating competence to express CA-ERBB2. Hearing thresholds were assessed with auditory brainstem response tests, and hearing recovery was assessed over a ninety-day period. Mice harboring CA-ERBB2 capability had similar hearing thresholds to control littermates prior to noise exposure, immediately after, and 30-days after. Sixty and ninety days after noise exposure, CA-ERBB2+ mice demonstrated a partial but significant reversal of NIHL threshold shifts at one in five frequencies tested, which was in the region of CA-ERBB2 expression. We evaluated inner and outer hair cell (IHC and OHC) survival, synaptic preservation, stereociliary morphology, and IHC cytoskeletal alterations with histological techniques. Improved IHC and OHC survival were observed in the basal cochlea. No differences were seen in synaptic numbers or IHC cytoskeletal alterations, but more stereocilia may have been preserved. These data indicate, for the first time, that ERBB2 signaling in supporting cells can promote hair cell survival and partial functional recovery, and that permanent threshold shifts from noise may be partially reversed in mice.

neuroscience↗

bioRxiv2018

Widespread alteration of protein autoinhibition in human cancers

Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

cancer biology↗

bioRxiv2017

Bimodal Spindle Orientation Drives Tissue Regularity in a Proliferating Epithelium

We investigated the relationship between proliferation and tissue topology in an epithelial tissue undergoing elongation. We found that cell division is not required for elongation of the early Drosophila follicular epithelium, but does drive the tissue towards optimal geometric packing. To increase tissue regularity, cell divisions are oriented in the planar axis, along the direction of tissue expansion. Planar division orientation is governed by apico-cortical tension, which aligns with tissue expansion but not with interphase cell shape elongation. Hertwigs Rule, which holds that cell elongation determines division orientation, is therefore broken in this tissue. We tested whether this observation could be explained by anisotropic activity of the conserved Pins/Mud spindle-orienting machinery, which controls division orientation in the apical-basal axis. We found that Pins/Mud does not participate in planar division orientation. Rather, tension translates into planar division orientation in a manner dependent on Canoe/Afadin, which links actomyosin to adherens junctions. These findings demonstrate that division orientation in different axes - apical-basal and planar - is controlled by distinct, independent mechanisms in a proliferating epithelium.\n\nSummary StatementRegularity in a proliferating epithelium requires cells to divorce division orientation from interphase shape, which they accomplish by using distinct mechanisms to orient divisions in the apical-basal and planar axes.

developmental biology↗