Biology subjects

Neagu, A.

Publications and source records attributed to Neagu, A..

6 recordsLinked to original sources

bioRxiv2026

let-7 miRNA and lin-46 mRNA are the two essential targets of the LIN28 RNA-binding protein in developmental timing

The RNA-binding protein (RBP) LIN28 is a key regulator of temporal cell fates, promoting stem cell identity and suppressing differentiation. It regulates the processing of the let-7 miRNA but additionally binds thousands of mRNAs, suggesting a model of coordinated regulation across many targets. Yet, direct evidence for such a network function is scarce for both LIN28 and other broadly binding RBPs. Here, we show that in C. elegans larvae, loss of LIN28 leaves the levels of most LIN28-bound transcripts unchanged. The only exceptions are the lin-46 mRNA and the let-7 miRNA. Comprehensive genetic analyses identify these two as the functionally essential LIN28 targets: lin-28; lin-46; let-7 triple null mutant animals exhibit complete suppression of the lin-28(0) precocious heterochronic phenotypes and recapitulate the retarded lin-46; let-7 double mutant phenotypes. Conversely, simultaneous overexpression of lin-46 and let-7 mimics LIN28 loss. Unexpectedly, LIN28 controls not only cell identity but also the tempo of development, using the same two targets. These findings establish a close functional link between the heterochronic pathway and the clock regulating developmental tempo and demonstrate that an RBP can achieve complex biological outcomes through a small set of targets.

developmental biology↗

bioRxiv2025

Shaping a Collaborative, Sustainable, Accessible, and Reproducible Future for Computational Modeling

The o2S2PARC platform is an open-source, extensible, and scalable cloud-based platform developed in the context of the U.S. National Institutes of Health SPARC program to support collaborative, sustainable, FAIR (findable, accessible, interoperable, reusable) and reproducible computational modeling and analysis. This publication presents the main features of o2S2PARC, its underlying approaches and philosophy, innovative aspects of the developed technologies, while also drawing attention to its rapid adoption. The paper showcases a variety of applications and use cases enabled by the platform. These include hybrid electromagnetic-electrophysiology simulations of neural interfaces, personalized brain and spinal cord stimulation planning, in silico device safety assessments, the training and application of AI systems (e.g., for model-predictive control and medical image segmentation), hybridized surrogate modeling and multi-objective optimization in high-dimensional parameter spaces, sensitive and unbiased validation of measurement devices, and interactive data analysis as paper supplements.

neuroscience↗

bioRxiv2025

Investigating the effectiveness of cannabidiol to mitigate the adverse consequences of exposure to neonatal procedural pain

Repeated painful procedures are associated with a multitude of effects on neurodevelopment in preterm infants, and current methods of neonatal pain management are unable to prevent the distress and long-term changes induced by these procedures. Cannabidiol (CBD) may be particularly effective for neonatal pain management because it reduces pain unpleasantness ratings, mitigates biological stress responses, and has minimal side effects in adults. However, there is limited research on the effects of neonatal CBD exposure. The present study investigated the efficacy of CBD treatment in mitigating behavioral responses to neonatal pain exposure. This was measured acutely through changes in ultrasonic vocalization (USV) emissions, as well as across development on long-term behavioral outcomes. We show that neonatal pain exposure decreased USV emission and increased adult anxiety-like behavior in male rats. Neonatal CBD treatment also decreased USVs in male pups but was unable to rescue the increased anxiety-like behavior in adulthood. Additionally, neonatal CBD increased baseline corticosterone levels in adult male subjects and decreased adult female body weight. More research is needed to determine whether CBD may be a safe and effective neonatal pain management medication. HighlightsO_LICBD reduced USV emissions on PD 2 and 3 in males, but not on later days C_LIO_LIPain exposure increased adult anxiety-like behavior in males C_LIO_LINeonatal CBD exposure resulted in decreased adult female body weight. C_LIO_LICBD had no permanent effects on measurements of neurodevelopment or adult behavior C_LIO_LICBD does not seem to mitigate effects of neonatal pain exposure C_LI

neuroscience↗

bioRxiv2023

Convergence of multiple RNA-silencing pathways on GW182/TNRC6

The RNA-binding protein TRIM71/LIN-41 is a phylogenetically conserved developmental regulator that functions in mammalian stem cell reprogramming, brain development and cancer. TRIM71 recognizes target mRNAs through hairpin motifs and silences them through molecular mechanisms that await identification. Here, we uncover that TRIM71 silences its targets by recruiting TNRC6/GW182, a core component of the miRNA-induced silencing complex (miRISC). Co-immunoprecipitation reveals interaction of TNRC6A with additional RNA-binding proteins and we demonstrate that AGO2, TRIM71, and UPF1 each recruit TNRC6 to specific, largely distinct sets of transcripts to silence them. As cellular TNRC6 levels are limiting, competition occurs among the silencing pathways, such that loss of AGO2 protein, or of AGO2 binding to TNRC6, enhances the activities of the other pathways. We conclude that a miRNA-like silencing activity is shared among different mRNA silencing pathways and that use of TNRC6 as a central hub provides a means to integrate their activities.

molecular biology↗

bioRxiv2019

Two parallel arms of the heterochronic pathway direct coordinated juvenile-to-adult transition through distinct LIN-29 isoforms

Robust organismal development relies on temporal coordination of disparate physiological processes. In Caenorhabditis elegans, the timely transition from juvenile to adult is controlled by the heterochronic pathway, a regulatory cascade of conserved proteins and small RNAs. The heterochronic pathway culminates in accumulation of the transcription factor LIN-29, which triggers coordinated execution of juvenile-to-adult (J/A) transition events. Here, we reveal that two LIN-29 isoforms fulfill distinct functions during the J/A transition. We show that the functional differences between the isoforms do not stem from differences in their sequences, but from their distinct spatiotemporal expression, and we propose that distinct LIN-29 dose sensitivities of the individual J/A transition events help to ensure their temporal ordering. We demonstrate that unique lin-29 isoform expression patterns are generated by the RNA-binding protein LIN-41 for lin-29a, and the transcription factor HBL-1 for lin-29b. By regulating both HBL-1 and LIN-41, the RNA-binding protein LIN-28 coordinates LIN-29 isoform activity. Thus, our findings reveal that a coordinated transition from juvenile to adult involves branching of a linear pathway to achieve timely control of multiple events.

developmental biology↗

bioRxiv2018

let-7 controls the transition to adulthood by releasing select transcriptional regulators from repression by LIN41

Development of multicellular organisms relies on faithful temporal control of cell fates. In Caenorhabditis elegans, the heterochronic pathway governs temporal patterning of somatic cells. This function may be phylogenetically conserved as several heterochronic genes have mammalian orthologues, and as the heterochronic let-7 miRNA and its regulator LIN28 appear to time the onset of puberty in mice and humans. Here, we have investigated how let-7 promotes the transition to adulthood in C. elegans. We find that let-7 controls each of three relevant processes, namely male and female sexual organ morphogenesis as well as changes in skin progenitor cell fates, through the same single target, lin-41. LIN41 in turn silences two pairs of targets post-transcriptionally, by binding and silencing their mRNAs. The EGR-type transcription factor LIN-29a and its co-factor, the NAB1/2 orthologous MAB-10, mediate control of progenitor cell fates and vulval integrity. By contrast, male tail development depends on regulation of the DM domain-containing transcription factors DMD-3 and MAB-3. Our results provide mechanistic insight into an exemplary temporal patterning pathway, demonstrate that let-7 - LIN41 function as a versatile regulatory module that can be connected to different outputs, and reveal how several levels of post-transcriptional regulation ultimately achieve effects through controlling transcriptional outputs.

developmental biology↗