Cell reports最新文献

Cell migration is a fundamental process during embryonic development. Most studies in vivo have focused on the migration of cells using the extracellular matrix (ECM) as their substrate for migration. In contrast, much less is known about how cells migrate on other cells, as found in early embryos when the ECM has not yet formed. Here, we show that lateral mesendoderm (LME) cells in the early zebrafish gastrula use the ectoderm as their substrate for migration. We show that the lateral ectoderm is permissive for the animal-pole-directed migration of LME cells, while the ectoderm at the animal pole halts it. These differences in permissiveness depend on the lateral ectoderm being more cohesive than the animal ectoderm, a property controlled by bone morphogenetic protein (BMP) signaling within the ectoderm. Collectively, these findings identify ectoderm tissue cohesion as one critical factor in regulating LME migration during zebrafish gastrulation.

Francois Jacob proposed that evolutionary novelty arises through incremental tinkering with pre-existing genetic mechanisms. Vertebrate evolution was predicated on pluripotency, the ability of embryonic cells to form somatic germ layers and primordial germ cells (PGCs). The origins of pluripotency remain unclear, as key regulators, such as Nanog, are not conserved outside of vertebrates. Given NANOG's role in mammalian development, we hypothesized that NANOG activity might exist in ancestral invertebrate genes. Here, we find that Vent from the hemichordate Saccoglossus kowalevskii exhibits NANOG activity, programming pluripotency in Nanog^-/- mouse pre-induced pluripotent stem cells (iPSCs) and NANOG-depleted axolotl embryos. Vent from the cnidarian Nematostella vectensis showed partial activity, whereas Vent from sponges and vertebrates had no activity. VENTX knockdown in axolotls revealed a role in germline-competent mesoderm, which Saccoglossus Vent could rescue but Nematostella Vent could not. This suggests that the last deuterostome ancestor had a Vent gene capable of programming pluripotency and germline competence.

Memories involving the hippocampus can take several days to consolidate, challenging efforts to uncover the neuronal signatures underlying this process. Here, we use calcium imaging in freely moving mice to track the hippocampal dynamics underlying memory consolidation across a 10-day contextual fear conditioning task. We find two neural signatures that emerge following learning and predict memory performance: context-specific place field remapping and coordinated neural activity prior to memory recall (freezing). To test whether these signatures support memory consolidation, we pharmacologically induced amnesia in separate mice by administering anisomycin, a protein synthesis inhibitor, immediately following learning. We find that anisomycin paradoxically accelerates cell turnover. Anisomycin also arrests learning-related remapping and blocks coordinated activity predictive of memory-related freezing behavior, effects that are likewise absent in untreated mice that exhibit poor memory expression. We conclude that context-specific place field remapping and the development of coordinated ensemble activity underlie contextual memory consolidation.

Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracellular space following neuronal injury. While NfL has been extensively studied as a disease biomarker, the underlying release mechanisms and role in neurodegeneration remain poorly understood. Here, we find that neurons secrete low baseline levels of NfL, while neuronal damage triggers calpain-driven proteolysis and release of fragmented NfL. Secreted NfL activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize in vivo single-cell RNA sequencing to profile brain cells after injection of recombinant NfL into the mouse hippocampus and find robust macrophage and microglial responses. Consistently, NfL knockout mice ameliorate microgliosis and delay symptom onset in the SOD1 mouse model of amyotrophic lateral sclerosis (ALS). Our results show that released NfL can activate myeloid cells in the brain and is, thus, a potential therapeutic target for neurodegenerative diseases.

Myeloid cells play vital roles in homeostasis and immune responses in vertebrates, but the developmental pathway underlying their lineage diversity remains elusive. Here, we construct a single-cell transcriptional map of myeloid progenitors from mouse bone marrow and conduct cross-species and developmental analyses across human, monkey, mouse, and zebrafish. We uncover a conserved specification program separating the eosinophil-basophil-mast cell (EBM) lineage and neutrophil-monocyte (NM) lineage, reclassifying myeloid cells beyond the conventional granulocytic and monocytic framework. By generating Ikzf2-EGFP reporter mice, we identify IKZF2 as a priming marker for EBM lineage specification. Ikzf2-EGFP⁺ and Ikzf2-EGFP^- granulocyte-monocyte progenitors (GMPs) exhibit distinct potential to generate EBM and NM lineages, and Ikzf2-EGFP expression robustly distinguishes their progenies. Additionally, we demonstrate that lineage specification emerges early during myelopoiesis. These findings provide a redefined perspective on myeloid lineage ontogeny, highlighting the conservation of lineage specification and offering insights into the understanding and therapeutic development of myelopoiesis.

Climate-change-induced extreme heat and drought increasingly threaten plant growth and development, with a particularly significant impact on sexual reproduction. Heat and drought stress can disrupt key stages of plant sexual reproduction, including flowering time, gametophyte development, pollination, and seed formation, leading to infertility and substantial yield reductions in crops. This review systematically summarizes the latest research on the effects of heat and drought stress on various stages of plant sexual reproduction and proposes specific strategies to mitigate the agricultural hazards posed by these stresses. By providing an in-depth analysis of the underlying mechanisms and regulatory networks, this review offers a theoretical basis for advancing fundamental research and optimizing agricultural practices to address the severe challenges climate change presents to agriculture.

Astrocytic interferon (IFN)γ signaling is associated with reduced neuroinflammation; however, downstream effectors responsible for regulating this protection are unknown. Here, we identify an IFN-specific transcription factor, basic leucine zipper ATF-like transcription factor (BATF)2, that plays a key role in modulating the consequences of IFNγ signaling in astrocytes. Chromatin immunoprecipitation sequencing revealed that BATF2 binds and prevents the overexpression of IFN regulatory factor (IRF)1 and IRF1 targets such as caspase-1. We also show that Batf2^-/- mice exhibit exacerbated clinical disease severity in a murine model of central nervous system autoimmunity and express increased astrocyte-specific IRF1 and caspase-1, suggesting an amplified IFN response in vivo. Additionally, we demonstrate that BATF2 is expressed primarily in astrocytes within multiple sclerosis lesions and that this expression is colocalized with IRF1. Collectively, our results further support evidence of protective functions for IFNγ and implicate BATF2 as a key suppressor of overactive immune signaling in astrocytes during neuroinflammation.

Streptomyces albidoflavus is a widely used strain for natural product discovery and production through heterologous biosynthetic gene clusters (BGCs). However, the transcriptional regulatory network (TRN) and its impact on secondary metabolism remain poorly understood. Here, we characterize the TRN using independent component analysis on 218 RNA sequencing (RNA-seq) transcriptomes across 88 unique growth conditions. We identify 78 independently modulated sets of genes (iModulons) that quantitatively describe the TRN across diverse conditions. Our analyses reveal (1) TRN adaptation to different growth conditions, (2) conserved and unique characteristics of the TRN across diverse lineages, (3) transcriptional activation of several endogenous BGCs, including surugamide, minimycin, and paulomycin, and (4) inferred functions of 40% of uncharacterized genes in the S. albidoflavus genome. These findings provide a comprehensive and quantitative understanding of the S. albidoflavus TRN, offering a knowledge base for further exploration and experimental validation.

Cardiac amyloidosis is a secondary phenomenon of an already pre-existing chronic condition. Whether cardiac amyloidosis represents one of the complications post myocardial infarction (MI) has yet to be fully understood. Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived serum amyloid A 3 (SAA3) monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from cardiac stromal cells (CSCs), which, in response to MI, activate the expression of a platelet aggregation-inducing type I transmembrane glycoprotein, Podoplanin (PDPN). CSC^PDPN+-derived small extracellular vesicles (sEVs) are enriched in SAA3, and exosomal SAA3 engages with macrophage by Toll-like receptor 2, triggering overproduction with consequent impaired clearance and aggregation of SAA3 monomers into rigid fibers. SAA3 amyloid deposits reduce cardiac contractility and increase scar stiffness. Inhibition of SAA3 aggregation by retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils and improves heart function post MI.

The choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or intraflagellar transport yields neonatal hydrocephalus, at least in part due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Sonic Hedgehog (Shh) signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by the Smoothened (Smo)/Gαi/cyclic AMP (cAMP) pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and motile cilia. Unlike most cilia that elongate during maturation, choroid plexus ciliary length decreases during development, causing a decline of Shh signaling intensity in the developing choroid plexus, a derepression of Aqp1 and Atp1a2, and, ultimately, increased CSF production. Hence, the developmental dynamics of choroid plexus multicilia dampens the Shh signaling intensity to promote CSF production.