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Results for “Lineage tracing”

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At least 145 records · Page 8Linked to original sources
PubMed1999

Dorsoventral patterning of the vertebrate limb: a process governed by multiple events.

In this review, we detail recent studies which have led to the first molecular insights into dorsoventral vertebrate limb patterning. In keeping with classical experiments which defined ectodermal-mesodermal signaling as an important component of limb bud dorsoventral axis specification, the genes identified to date to be critically important for proper dorsoventral limb patterning include both ectodermally and mesodermally expressed cell:cell signaling molecules and transcription factors. A surprising complexity to dorsoventral vertebrate limb patterning has been revealed by gene targeting in the mouse and lineage tracing in the chick, with current models suggesting that the dorsoventral limb axis is specified by distinct mechanisms in the proximal versus distal limb.

Animals↗
PubMed1993

The homeobox gene goosecoid controls cell migration in Xenopus embryos.

Goosecoid (gsc), a homeobox gene expressed specifically in the dorsal blastopore lip of the Xenopus gastrula, is considered to play an important role in Spemann's organizer phenomenon. Lineage tracing and time-lapse microscopy were used to follow the fate of embryonic cells microinjected with gsc mRNA. Microinjected gsc has non-cell autonomous effects, recruiting neighboring uninjected cells into a twinned dorsal axis. Ectopic expression of gsc mRNA in ventral blastomeres as well as overexpression of gsc in dorsal blastomeres leads to cell movement toward the anterior of the embryo. The results suggest a function for gsc in the control of gastrulation movements in groups of cells, but not in dissociated cells, and demonstrate that a vertebrate homeobox gene can regulate region-specific cell migration.

Animals↗
PubMed1995

RNA detection using non-radioactive in situ hybridization.

Methods of non-radioactive in situ hybridization to RNA now enable the simultaneous detection of two RNAs in the same tissue. Sensitivity has been increased by several modifications, including the use of the polymerase chain reaction. Recently, in situ hybridization has been combined with lineage tracing to determine the origin of cells expressing a specific gene.

Animals↗
PubMed2026

Athero-oncology: Vascular smooth muscle cell tumor-like transformation in atherosclerosis and therapeutic opportunities.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, and its pathogenesis and treatment strategies remain major challenges. Recent advances in single-cell RNA sequencing and lineage tracing have revealed that vascular smooth muscle cells (VSMCs) are not merely passive structural components of atherosclerotic plaques, but highly plastic participants that undergo clonal expansion, phenotypic modulation, and transdifferentiation into functionally diverse cell states. These findings have prompted the emergence of an "athero-oncology" framework, which explores selected tumor-like cellular programs in VSMCs during AS without equating atherosclerosis with cancer. In this review, we summarize the evidence supporting VSMC-derived clonal expansion and phenotypic diversification in atherosclerotic lesions and discuss key mechanisms involved in this process, including proliferative expansion and survival programs, metabolic reprogramming, epigenetic regulation, DNA damage and genomic stress, VSMC senescence, pathological angiogenesis, and remodeling of the inflammatory and immune microenvironment. We further highlight shared signaling pathways between VSMC-driven plaque remodeling and tumor biology, while emphasizing fundamental differences between AS and malignant disease in growth limitation, mutational burden, metastatic potential, and clinical behavior. Finally, we discuss oncology-inspired therapeutic opportunities and boundaries, including pathway-level targeting of proliferative, metabolic, epigenetic, and inflammatory programs, as well as the risks of directly repurposing anticancer therapies for chronic vascular disease. This framework may provide new insights into vascular biology and therapeutic development.

atherosclerosis↗
PubMed2005

Endocrine pancreatic tissue plasticity in obese humans is associated with cytoplasmic expression of PBX-1 in pancreatic ductal cells.

In vivo lineage tracing experiments in mice have recently cast doubt on the potential islet neogenesis from ductal precursors in adult mammals. We examined, in human obesity, a model for pancreatic endocrine tissue plasticity, the gene and protein expression of PBX-1-a transcription factor expressed in regenerating rat ductules and potentially implicated in the pancreatic development, alone or in association with PDX-1. When comparing gene expression, by quantitative real-time RT-PCR, in pancreatic exocrine tissue from obese non-diabetic subjects with increased islet mass, we found that Pbx-1 and Pdx-1 were up-regulated (5.9+/-1.2 and 2.4+/-0.6 versus non-obese). Immunohistochemistry confirmed PBX-1 over-expression and its cytoplasmic sequestration in ductal cells of obese subjects, associated with pronounced islet neogenesis (cytokeratin 19/chromogranin A double labeling). cDNA microarray analysis also showed up-regulation of other genes implicated in islet regeneration, including betacellulin, laminin, TGFa, NeuroD1, Pax6, substantiating the role of the islet neogenesis pathway in human obesity.

Adaptation, Physiological↗
PubMed2026

Stress-driven strategic games in cancer.

Tumor cells face chronic genotoxic, metabolic, hypoxic, and immune stress that shapes their evolution. While stress-response molecular pathways are well characterized, cancer biology lacks a predictive framework for how cells select among alternative adaptive strategies and how these selections interact to produce tumor-level behavior. We propose that evolutionary game theory, previously applied to cooperation in cancer, should be extended to position stress adaptation itself as the organizing principle of tumor evolution. In this framework, stress-adaptive strategies constitute frequency-dependent games whose payoffs depend on population composition. We introduce a three-level distinction between cell states (transcriptional snapshots), game states (local configurations of stress and neighbor composition that define the active payoff structure), and cell strategies (conditional behavioral policies mapping game states to fitness-relevant outputs). This perspective explains the maintenance of intratumor heterogeneity through frequency-dependent selection, the reversibility of resistance through bet-hedging dynamics, and therapy resistance as an equilibrium outcome rather than genetic inevitability. Integrating insights from single-cell genomics, spatial profiling, and lineage tracing, we outline testable predictions and experimental approaches for measuring payoff structures. Therapeutically, the framework suggests exploiting adaptive trade-offs, restricting phenotypic plasticity, and reshaping competitive landscapes. Re-framing cancer as an evolving game of stress adaptation provides a unifying structure for predictive oncology.

Animals↗
PubMed2005

Regulatory mechanisms of cortical laminar development.

The developing forebrain exhibits a high degree of spatiotemporal regulation of proliferation and cell cycle exit in progenitor cells of its proliferative zones. This results in the balanced deployment of progenitors between asymmetric division, yielding postmitotic neurons and cycling progenitors, and terminal symmetric division, resulting in differentiated daughter cells. Radial glia have been demonstrated to be the principal neuronal progenitor of the cortical primordium. Lineage tracing studies employing real-time imaging in vivo have enhanced understanding of neuronal production and migration. Cortical projection neurons have been shown to arise from the radial migration of precursors generated in the dorsal telencephalon, whereas most interneurons derive from the germinal zone of the ventral telencephalon and migrate tangentially into the primordial cortex. Cells from both populations undergo diverse and complex sequences of migratory activity. Neuronal phenotypic potential is informed in progenitors prior to their last cell division. Laminar and regional fate potential of progenitors becomes progressively restricted with successive cell cycles. This process of neuronal fate specification is regulated by the interaction of programs of transcriptional regulation with extrinsic patterning signals according to time and region of the proliferative zone in which the final mitotic cycle occurs.

Animals↗
PubMed2006

Neuroendocrinology of protochordates: insights from Ciona genomics.

The genome for two species of Ciona is available making these tunicates excellent models for studies on the evolution of the chordates. In this review most of the data is from Ciona intestinalis, as the annotation of the C. savignyi genome is not yet available. The phylogenetic position of tunicates at the origin of the chordates and the nature of the genome before expansion in vertebrates allows tunicates to be used as a touchstone for understanding genes that either preceded or arose in vertebrates. A comparison of Ciona, a sea squirt, to other model organisms such as a nematode, fruit fly, zebrafish, frog, chicken and mouse shows that Ciona has many useful traits including accessibility for embryological, lineage tracing, forward genetics, and loss- or gain-of-function experiments. For neuroendocrine studies, these traits are important for determining gene function, whereas the availability of the genome is critical for identification of ligands, receptors, transcription factors and signaling pathways. Four major neurohormones and their receptors have been identified by cloning and to some extent by function in Ciona: gonadotropin-releasing hormone, insulin, insulin-like growth factor, and cionin, a member of the CCK/gastrin family. The simplicity of tunicates should be an advantage in searching for novel functions for these hormones. Other neuroendocrine components that have been annotated in the genome are a multitude of receptors, which are available for cloning, expression and functional studies.

Animals↗
PubMed2004

The anterior-posterior axis emerges respecting the morphology of the mouse embryo that changes and aligns with the uterus before gastrulation.

BACKGROUND: When the anterior-posterior axis of the mouse embryo becomes explicit at gastrulation, it is almost perpendicular to the long uterine axis. This led to the belief that the uterus could play a key role in positioning this future body axis. RESULTS: Here, we demonstrate that when the anterior-posterior axis first emerges it does not respect the axes of the uterus but, rather, the morphology of the embryo. Unexpectedly, the emerging anterior-posterior axis is initially aligned not with the long, but the short axis of the embryo. Then whether the embryo develops in vitro or in utero, the anterior-posterior axis becomes aligned with the long axis of embryo just prior to gastrulation. Of three mechanisms that could account for this apparent shift in anterior-posterior axis orientation-cell migration, spatial change of gene expression, or change in embryo shape-lineage tracing studies favor a shape change accompanied by restriction of the expression domain of anterior markers. This property of the embryo must be modulated by interactions with the uterus as ultimately the anterior-posterior and long axes of the embryo align with the left-right uterine axis. CONCLUSIONS: The emerging anterior-posterior axis relates to embryo morphology rather than that of the uterus. The apparent shift in its orientation to align with the long embryonic axis and with the uterus is associated with a change in embryo shape and a refinement of anterior gene expression pattern. This suggests an interdependence between anterior-posterior gene expression, the shape of the embryo, and the uterus.

Animals↗
PubMed2006

Development of the zebrafish lymphatic system requires VEGFC signaling.

Lymphangiogenesis results in the formation of a vascular network distinct from arteries and veins that serves to drain interstitial fluid from surrounding tissues and plays a pivotal role in the immune defense of vertebrates as well as in the progression of cancer and other diseases . In mammals, lymph vessels are lined by endothelial cells possibly sprouting from embryonic veins, and their development appears to be critically dependent on the function of PROX1 and VEGFC signaling . The existence of a lymphatic system in teleosts has been a matter of debate for decades. Here we show on the morphological, molecular, and functional levels that zebrafish embryos develop a lymphatic vasculature that serves to retrieve components of the interstitium to the lymph system. We demonstrate the existence of vessels that are molecularly and functionally distinct from blood vessels and show that the development of these vessels depends on Vegfc and VEGFR-3/Flt4 signaling. These findings imply that the molecular components controlling lymphangiogenesis in zebrafish and mammals are conserved and that the zebrafish lymphatic system develops early enough to allow in vivo observations, lineage tracing, and genetic as well as pharmacological screens.

Angiopoietin-2↗
PubMed2005

The chick; a great model system becomes even greater.

The chick embryo has a long and distinguished history as a major model system in developmental biology and has also contributed major concepts to immunology, genetics, virology, cancer, and cell biology. Now, it has become even more powerful thanks to several new technologies: in vivo electroporation (allowing gain- and loss-of-function in vivo in a time- and space-controlled way), embryonic stem (ES) cells, novel methods for transgenesis, and the completion of the first draft of the sequence of its genome along with many new resources to access this information. In combination with classical techniques such as grafting and lineage tracing, the chicken is now one of the most versatile experimental systems available.

Animals↗
PubMed2026

Stromal Hedgehog Signaling Drives Segment-Specific Malignant Transformation of Gastrointestinal Stem Cells by Producing Bone Morphogenetic Protein Antagonists.

BACKGROUND & AIMS: Hedgehog signaling plays a complex role in epithelial-stromal interactions, but its effects on gastrointestinal stem cells mediated by heterogeneous stromal cell populations remain incompletely defined. Here, we investigate how stromal Hedgehog signaling regulates gastric stem cells and tumorigenesis in a segment-specific manner. METHODS: We genetically activated Hedgehog signaling in distinct stromal cell lineages using Col1a2-, Pdgfra-, Gli1-, Acta2-, and Prrx1-CreERT mouse lines, combined with lineage tracing, RNA sequencing, chromatin immunoprecipitation-quantitative polymerase chain reaction, and pharmacologic interventions. Human gastric cancer data from The Cancer Genome Atlas were also analyzed. RESULTS: We show that genetic activation of Hedgehog signaling in stromal cells marked by Col1a2, Pdgfra, or Gli1, but not by Acta2, induces tumorigenesis in the stomach and gastroesophageal junction, but not in the small or large intestine. Hedgehog signaling increases the expression of multiple bone morphogenetic protein antagonists in gastric but not colonic stromal cells, via Gli1-mediated transcription. These bone morphogenetic protein antagonists, in turn, activate Wnt/β-catenin signaling in gastric stem cells, driving their proliferation and initiating gastric cancer expressing CD44 and Sox9, but not Lgr5. Activating bone morphogenetic protein or inhibiting Wnt signaling blocks tumor initiation. Analysis of patient data from The Cancer Genome Atlas reveals elevated Hedgehog signaling in gastric cancers, which correlates with suppressed bone morphogenetic protein signaling. CONCLUSIONS: These findings uncover a gastrointestinal segment-specific oncogenic role for Hedgehog signaling in Col1a2+Acta2- stromal cells, mediated through the bone morphogenetic protein-Wnt-β-catenin axis.

BMP Antagonists↗
PubMed2004

Origin of exocrine pancreatic cells from nestin-positive precursors in developing mouse pancreas.

During pancreatic development, endocrine and exocrine cell types arise from common precursors in foregut endoderm. However, little information is available regarding regulation of pancreatic epithelial differentiation in specific precursor populations. We show that undifferentiated epithelial precursors in E10.5 mouse pancreas express nestin, an intermediate filament also expressed in neural stem cells. Within developing pancreatic epithelium, nestin is co-expressed with pdx1 and p48, but not ngn3. Epithelial nestin expression is extinguished upon differentiation of endocrine and exocrine cell types, and no nestin-positive epithelial cells are observed by E15.5. In E10.5 dorsal bud explants, activation of EGF signaling results in maintenance of undifferentiated nestin-positive precursors at the expense of differentiated acinar cells, suggesting a precursor/progeny relationship between these cell types. This relationship was confirmed by rigorous lineage tracing studies using nestin regulatory elements to drive Cre-mediated labeling of nestin-positive precursor cells and their progeny. These experiments demonstrate that a nestin promoter/enhancer element containing the second intron of the mouse nestin locus is active in undifferentiated E10.5 pancreatic epithelial cells, and that these nestin-positive precursors contribute to the generation of differentiated acinar cells. As in neural tissue, nestin-positive cells act as epithelial progenitors during pancreatic development, and may be regulated by EGF receptor activity.

Animals↗
PubMed2006

Targeted ablation of beta cells in the embryonic zebrafish pancreas using E. coli nitroreductase.

In order to generate a zebrafish model of beta cell regeneration, we have expressed an Escherichia coli gene called nfsB in the beta cells of embryonic zebrafish. This bacterial gene encodes a nitroreductase (NTR) enzyme, which can convert prodrugs such as metronidazole (Met) to cytotoxins. By fusing nfsB to mCherry, we can simultaneously render beta cells susceptible to prodrug and visualize Met dependent cell ablation. We show that the neighboring alpha and delta cells are unaffected by prodrug treatment and that ablation is beta cell specific. Following drug removal and 36h of recovery, beta cells regenerate. Using ptf1a morphants, it is clear that this beta cell recovery occurs independently of the presence of the exocrine pancreas. Also, by using photoconvertible Kaede to cell lineage trace and BrdU incorporation to label proliferation, we investigate mechanisms for beta regeneration. Therefore, we have developed a unique resource for the study of beta cell regeneration in a living vertebrate organism, which will provide the opportunity to conduct large-scale screens for pharmacological and genetic modifiers of beta cell regeneration.

Animals↗
PubMed2005

Exclusive expression of hedgehog in small micromere descendants during early embryogenesis in the sea urchin, Hemicentrotus pulcherrimus.

Hedgehog (hh) is a multifunctional extracellular protein, and known as an essential signal molecule in morphogenetic movement in animal embryos. We have cloned, sequenced, and studied dynamic localization of Hphh, a hedgehog homologue of the sea urchin, Hemicentrotus pulcherrimus. The origin of Hphh transcribing cells was also verified during early embryogenesis. The amino acid sequence of Hphh shows high homology to Lvhh, an hh homologue cloned in the sea urchin, Lytechinus variegatus. Reverse transcriptase polymerase chain reaction showed that the transcription of Hphh occurred at and after 19 h post-fertilization (19 hpf) mesenchyme blastula stage until, at least, 69 hpf 4-arm pluteus stage. Whole mount in situ hybridization showed Hphh transcription sites in a few cells at the tip of archenteron in 30 hpf gastrulae. At around 45 hpf 2-arm pluteus stage, the number of Hphh transcribed cells was 8, and unequally split to two groups, 5 cells in left coelomic sac and 3 cells in right coelomic sac. A cell lineage tracing by staining the small micromeres with 5-Bromo-2-deoxyuridine showed that Hphh was transcribed exclusively in all the small micromere descendants and comprised the coelomic sacs in 69 hpf plutei.

Amino Acid Sequence↗
PubMed2005

Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum.

The molecular machinery governing glutamatergic-GABAergic neuronal subtype specification is unclear. Here we describe a cerebellar mutant, cerebelless, which lacks the entire cerebellar cortex in adults. The primary defect of the mutant brains was a specific inhibition of GABAergic neuron production from the cerebellar ventricular zone (VZ), resulting in secondary and complete loss of external germinal layer, pontine, and olivary nuclei during development. We identified the responsible gene, Ptf1a, whose expression was lost in the cerebellar VZ but was maintained in the pancreas in cerebelless. Lineage tracing revealed that two types of neural precursors exist in the cerebellar VZ: Ptf1a-expressing and -nonexpressing precursors, which generate GABAergic and glutamatergic neurons, respectively. Introduction of Ptf1a into glutamatergic neuron precursors in the dorsal telencephalon generated GABAergic neurons with representative morphological and migratory features. Our results suggest that Ptf1a is involved in driving neural precursors to differentiate into GABAergic neurons in the cerebellum.

Age Factors↗
PubMed2005

Molecular inroads into the anterior heart field.

In 2001, three research groups described a previously unrecognized population of progenitor cells in pharyngeal mesoderm that gives rise to myocardium at the arterial pole of the heart. In the last 4 years, the major importance of the cellular contribution of pharyngeal mesoderm to normal and pathologic heart development has become apparent. Lineage-tracing experiments have defined the extent to which pharyngeal progenitor cells colonize the heart, revealing a contribution to venous, as well as arterial, pole myocardium; in addition, major molecular inroads have been made into understanding gene regulation in pharyngeal myocardial progenitor cells, implicating forkhead, Gata, LIM homeodomain, MEF2, SMAD, and T-box transcription factors. The key role of the anterior heart field during normal heart development is underscored by the demonstration that both direct and indirect perturbation of myocardial progenitor cells in pharyngeal mesoderm result in congenital heart disease.

Animals↗
PubMed2004

Neurogenin3 delineates the earliest stages of spermatogenesis in the mouse testis.

In mammalian testis, a typical stem cell system ensures continuous spermatozoa production. Lines of experiments have demonstrated that stem cell activity resides in the most primitive small subset of germ cells, that is, A(s) (A(single)), A(pr) (A(paired)), and A(al) (A(aligned)) spermatogonia, also collectively called undifferentiated spermatogonia. However, their cellular or molecular nature is largely to be elucidated because a gene that is specifically expressed in these cells has not yet been identified, which makes it difficult to study them. In this study, we demonstrate that a class B basic helix-loop-helix (bHLH) transcription factor neurogenin3 (ngn3) is expressed specifically in A(s), A(pr), and A(al) spermatogonia because ngn3 is expressed in c-Kit negative spermatogonia throughout the seminiferous cycle, and transgenic labeling with GFP revealed connection of 1, 2, 4, 8, 16, or 32 ngn3-positive cells via intercellular bridges. ngn3 is first expressed at the prepubertal stage in c-Kit negative prespermatogonia. Lineage tracing, using the Cre-loxP system, demonstrates that ngn3-positive germ cells give rise to eventually all the spermatogenesis in mature testis. To our knowledge, ngn3 is the first reported gene that delineates these earliest stages of spermatogenesis. Considering its molecular nature, ngn3 could be involved in their differentiation control. Moreover, visualization with GFP and targeting expression of exogenous genes are valuable tools to investigate the mammalian spermatogenic stem cell system.

Animals↗