PLoS Biology最新文献

Formation of functional organs requires cell-cell communication between different cell lineages and failure in this communication can result in severe developmental defects. Hundreds of possible interacting pairs of proteins are known, but identifying the interacting partners that ensure a specific interaction between 2 given cell types remains challenging. Here, we use the Drosophila leg model and our cell type-specific transcriptomic data sets to uncover the molecular mediators of cell-cell communication between tendon and muscle precursors. Through the analysis of gene expression signatures of appendicular muscle and tendon precursor cells, we identify 2 candidates for early interactions between these 2 cell populations: Amalgam (Ama) encoding a secreted protein and Neurotactin (Nrt) known to encode a membrane-bound protein. Developmental expression and function analyses reveal that: (i) Ama is expressed in the leg myoblasts, whereas Nrt is expressed in adjacent tendon precursors; and (ii) in Ama and Nrt mutants, myoblast-tendon cell-cell association is lost, leading to tendon developmental defects. Furthermore, we demonstrate that Ama acts downstream of the FGFR pathway to maintain the myoblast population by promoting cell survival and proliferation in an Nrt-independent manner. Together, our data pinpoint Ama and Nrt as molecular actors ensuring early reciprocal communication between leg muscle and tendon precursors, a prerequisite for the coordinated development of the appendicular musculoskeletal system.

Mutualistic ecological networks can suddenly transition to undesirable states due to small changes in environmental conditions. Recovering from such a collapse can be difficult as restoring the original environmental conditions may be infeasible. Additionally, such networks can also exhibit a phenomenon known as hysteresis, whereby the system could exhibit multiple states under the same environmental conditions, implying that ecological networks may not recover. Here, we attempted to revive collapsed mutualistic networks to a high-functioning state from a single species, using concepts from signal propagation theory and an eco-evolutionary model based on network structures of 115 empirical plant-pollinator networks. We found that restoring the environmental conditions rarely aided in recovery of collapsed networks, but a positive relationship between recovering pollinator density and network nestedness emerged, which was qualitatively supported by empirical plant-pollinator restoration data. In contrast, network resurrection from a collapsed state in undesirable environmental conditions where restoration has minimal impacts could be readily achieved by perturbing a single species or a few species that control the response of the dynamical networks. Additionally, nestedness in networks and a moderate amount of trait variation could aid in the revival of networks even in undesirable environmental conditions. Our work suggests that focus should be applied to a few species whose dynamics could be steered to resurrect entire networks from a collapsed state and that network architecture could play a crucial role in reviving collapsed plant-pollinator networks.

Distinguishing reality from hallucinations requires efficient monitoring of agency. It has been hypothesized that a copy of motor signals, termed efference copy (EC) or corollary discharge (CD), suppresses sensory responses to yield a sense of agency; impairment of the inhibitory function leads to hallucinations. However, how can the sole absence of inhibition yield positive symptoms of hallucinations? We hypothesize that selective impairments in functionally distinct signals of CD and EC during motor-to-sensory transformation cause the positive symptoms of hallucinations. In an electroencephalography (EEG) experiment with a delayed articulation paradigm in schizophrenic patients with (AVHs) and without auditory verbal hallucinations (non-AVHs), we found that preparing to speak without knowing the contents (general preparation) did not suppress auditory responses in both patient groups, suggesting the absent of inhibitory function of CD. Whereas, preparing to speak a syllable (specific preparation) enhanced the auditory responses to the prepared syllable in non-AVHs, whereas AVHs showed enhancement in responses to unprepared syllables, opposite to the observations in the normal population, suggesting that the enhancement function of EC is not precise in AVHs. A computational model with a virtual lesion of an inhibitory inter-neuron and disproportional sensitization of auditory cortices fitted the empirical data and further quantified the distinct impairments in motor-to-sensory transformation in AVHs. These results suggest that "broken" CD plus "noisy" EC causes erroneous monitoring of the imprecise generation of internal auditory representation and yields auditory hallucinations. Specific impairments in functional granularity of motor-to-sensory transformation mediate positivity symptoms of agency abnormality in mental disorders.

The packaging of genomic RNA (gRNA) into retroviral particles relies on the specific recognition by the Gag precursor of packaging signals (Psi), which maintain a complex secondary structure through long-range interactions (LRIs). However, it remains unclear whether the binding of Gag to Psi alone is enough to promote RNA packaging and what role LRIs play in this process. Using mouse mammary tumor virus (MMTV), we investigated the effects of mutations in 4 proposed LRIs on gRNA structure and function. Our findings revealed the presence of an unsuspected extended LRI, and hSHAPE revealed that maintaining a wild-type-like Psi structure is crucial for efficient packaging. Surprisingly, filter-binding assays demonstrated that most mutants, regardless of their packaging capability, exhibited significant binding to Pr77Gag, suggesting that Gag binding to Psi is insufficient for efficient packaging. Footprinting experiments indicated that efficient RNA packaging is promoted when Pr77Gag binds to 2 specific sites within Psi, whereas binding elsewhere in Psi does not lead to efficient packaging. Taken together, our results suggest that the 3D structure of the Psi/Pr77Gag complex regulates the assembly of viral particles around gRNA, enabling effective discrimination against other viral and cellular RNAs that may also bind Gag efficiently.

Within species, vocal and auditory systems presumably coevolved to converge on a critical temporal acoustic structure that can be best produced and perceived. While dogs cannot produce articulated sounds, they respond to speech, raising the question as to whether this heterospecific receptive ability could be shaped by exposure to speech or remains bounded by their own sensorimotor capacity. Using acoustic analyses of dog vocalisations, we show that their main production rhythm is slower than the dominant (syllabic) speech rate, and that human-dog-directed speech falls halfway in between. Comparative exploration of neural (electroencephalography) and behavioural responses to speech reveals that comprehension in dogs relies on a slower speech rhythm tracking (delta) than humans' (theta), even though dogs are equally sensitive to speech content and prosody. Thus, the dog audio-motor tuning differs from humans', and we hypothesise that humans may adjust their speech rate to this shared temporal channel as means to improve communication efficacy.

The optimization of brain circuit connectivity based on initial environmental input occurs during critical periods characterized by sensory experience-dependent, temporally restricted, and transiently reversible synapse elimination. This precise, targeted synaptic pruning mechanism is mediated by glial phagocytosis. Serotonin signaling has prominent, foundational roles in the brain, but functions in glia, or in experience-dependent brain circuit synaptic connectivity remodeling, have been relatively unknown. Here, we discover that serotonergic signaling between glia is essential for olfactory experience-dependent synaptic glomerulus pruning restricted to a well-defined Drosophila critical period. We find that experience-dependent serotonin signaling is restricted to the critical period, with both (1) serotonin production and (2) 5-HT2A receptors specifically in glia, but not neurons, absolutely required for targeted synaptic glomerulus pruning. We discover that glial 5-HT2A receptor signaling limits the experience-dependent synaptic connectivity pruning in the critical period and that conditional reexpression of 5-HT2A receptors within adult glia reestablishes "critical period-like" experience-dependent synaptic glomerulus pruning at maturity. These results reveal an essential requirement for glial serotonergic signaling mediated by 5-HT2A receptors for experience-dependent synapse elimination.

Mycobacterium tuberculosis (Mtb) releases the unusual terpene nucleoside 1-tuberculosinyladenosine (1-TbAd) to block lysosomal function and promote survival in human macrophages. Using conventional approaches, we found that genes Rv3377c and Rv3378c, but not Rv3376, were necessary for 1-TbAd biosynthesis. Here, we introduce linear models for mass spectrometry (limms) software as a next-generation lipidomics tool to study the essential functions of lipid biosynthetic enzymes on a whole-cell basis. Using limms, whole-cell lipid profiles deepened the phenotypic landscape of comparative mass spectrometry experiments and identified a large family of approximately 100 terpene nucleoside metabolites downstream of Rv3378c. We validated the identity of previously unknown adenine-, adenosine-, and lipid-modified tuberculosinol-containing molecules using synthetic chemistry and collisional mass spectrometry, including comprehensive profiling of bacterial lipids that fragment to adenine. We tracked terpene nucleoside genotypes and lipid phenotypes among Mycobacterium tuberculosis complex (MTC) species that did or did not evolve to productively infect either human or nonhuman mammals. Although 1-TbAd biosynthesis genes were thought to be restricted to the MTC, we identified the locus in unexpected species outside the MTC. Sequence analysis of the locus showed nucleotide usage characteristic of plasmids from plant-associated bacteria, clarifying the origin and timing of horizontal gene transfer to a pre-MTC progenitor. The data demonstrated correlation between high level terpene nucleoside biosynthesis and mycobacterial competence for human infection, and 2 mechanisms of 1-TbAd biosynthesis loss. Overall, the selective gain and evolutionary retention of tuberculosinyl metabolites in modern species that cause human TB suggest a role in human TB disease, and the newly discovered molecules represent candidate disease-specific biomarkers.

New mutations provide the source of all genetic variation but their impact on trait variation remains poorly understood. A new study published in PLOS Biology addresses this question, finding that new mutations exert only weak effects on some traits in mice.

The nonsense-mediated mRNA decay (NMD) pathway clears eukaryotic cells of mRNAs containing premature termination codons (PTCs) or normal stop codons located in specific contexts. It therefore plays an important role in gene expression regulation. The precise molecular mechanism of the NMD pathway has long been considered to differ substantially from yeast to metazoa, despite the involvement of universally conserved factors such as the central ATP-dependent RNA-helicase Upf1. Here, we describe the crystal structure of the yeast Upf1 bound to its recently identified but yet uncharacterized partner Nmd4, show that Nmd4 stimulates Upf1 ATPase activity and that this interaction contributes to the elimination of NMD substrates. We also demonstrate that a region of Nmd4 critical for the interaction with Upf1 in yeast is conserved in the metazoan SMG6 protein, another major NMD factor. We show that this conserved region is involved in the interaction of SMG6 with UPF1 and that mutations in this region affect the levels of endogenous human NMD substrates. Our results support the universal conservation of the NMD mechanism in eukaryotes.

Transport proteins play a crucial role in cellular metabolism and are central to many aspects of molecular biology and medicine. Determining the function of transport proteins experimentally is challenging, as they become unstable when isolated from cell membranes. Machine learning-based predictions could provide an efficient alternative. However, existing methods are limited to predicting a small number of specific substrates or broad transporter classes. These limitations stem partly from using small data sets for model training and a choice of input features that lack sufficient information about the prediction problem. Here, we present SPOT, the first general machine learning model that can successfully predict specific substrates for arbitrary transport proteins, achieving an accuracy above 92% on independent and diverse test data covering widely different transporters and a broad range of metabolites. SPOT uses Transformer Networks to represent transporters and substrates numerically. To overcome the problem of missing negative data for training, it augments a large data set of known transporter-substrate pairs with carefully sampled random molecules as non-substrates. SPOT not only predicts specific transporter-substrate pairs, but also outperforms previously published models designed to predict broad substrate classes for individual transport proteins. We provide a web server and Python function that allows users to explore the substrate scope of arbitrary transporters.