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PubMed1991

Lineage of neurons and glia in chick dorsal root ganglia: analysis in vivo with a recombinant retrovirus.

We used retrovirus-mediated gene transfer to study the lineage of neural crest cells in chick embryos. Individual crest cells were infected before they migrated from the neural tube, and their clonal progeny were subsequently revealed in sensory ganglia and associated structures by a histochemical stain for the viral gene product (lacZ). We found that crest cells were multipotential in several respects. (1) Many clones contained both ventrolateral (VL) and dorsomedial (DM) neurons, which had been suggested to be lineally distinct. (2) Many clones contained both large and small neurons, which are known to innervate distinct targets. (3) Many clones contained multiple glial subtypes, e.g. both Schwann cells, which ensheath axons, and satellite cells, which ensheath neuronal somata. (4) Many clones contained both neurons and glial cells. On the other hand, a sizeable minority of clones was homogenous, e.g. they contained only neurons or only glial cells--suggesting that some progenitors may be, or become, restricted in potential. Finally, this study provides the first opportunity to compare directly the two methods currently available for tracing cell lineage in vertebrate embryos, retroviral infection and tracer injection: our results and those of Bronner-Fraser and Fraser (1989), who used the latter method, provide complementary but consistent views of crest lineage.

Animals↗

PubMed1989

Glutamine synthetase heterogeneous expression as a marker for the cellular lineage of preneoplastic and neoplastic liver populations.

The distribution of glutamine synthetase (GS) in rat liver and in putative preneoplastic and neoplastic lesions was studied at stages of hepatocarcinogenesis induced by diethylnitrosamine (DEN), 2-acetylaminofluorene (AAF) and aflatoxin B1 (AFB1) using immunohistochemistry. In control rats, GS was localized entirely to rings 1-3 cells deep surrounding the central veins. Exposure to DEN or AAF resulted in a reduction of these GS-positive (GS+) zones by 96 and 61% respectively, due to necrosis of the cells in this compartment, while AFB1 had little effect (less than 14%). At later times GS+ foci, adenomas and carcinomas developed in animals exposed to DEN or AAF, but not AFB1, corresponding to the acute effects. Small GS+ foci also identified by other phenotypic abnormalities (e.g. gamma-glutamyltransferase) were exclusively associated with the regenerating GS+ zone as were a few collections of GS+ hepatocytes, the nature of which was uncertain. Although accounting for a very small fraction (less than 3%) of total foci, these GS+ foci or GS+ hepatocytes apparently gave rise to a substantial fraction of adenomas that were GS+ (DEN: 43% and AAF: 33%) and an even higher percentage of GS+ carcinomas (DEN: 59% and AAF: 39%). No GS+ neoplasms were induced by AFB1. Statistical evaluation of these data strongly suggests that GS+ neoplasms originate through initiation of hepatocytes which possess this particular phenotype. Thus, GS might serve as a specific marker for tracing cell lineage relationships during hepatocarcinogensis. The GS+ phenotype which confers glutamine independence may also provide a growth advantage.

2-Acetylaminofluorene↗

PubMed2005

Evidence for the hemangioblast.

In recent years, numerous cellular and genetic studies have led to a better understanding of the developmental relationship between hematopoietic and endothelial cell lineages. Specifically, tracing cells expressing various genes such as Brachyury, Flk-1, or Scl has delineated the cellular sequence leading to hematopoietic and endothelial cell development from mesoderm. Moreover, in vitro as well as in vivo studies of invertebrate and vertebrate systems have established that hematopoietic and endothelial cells develop from a common progenitor, the hemangioblast. Finally, the presence of the hemangioblast has been confirmed in postnatal mice and humans. Further characterization of the hemangioblast, both embryo and postnatal, will be critical for a better understanding of the molecular events involved in hematopoietic and endothelial cell differentiation as well as for utilizing this cell population for clinical applications.

Animals↗

PubMed1988

Embryonic divergence of oligodendrocyte and astrocyte lineages in developing rat cerebrum.

Oligodendrocyte and astrocyte lineages were traced in rat forebrain sections using single- and double-label immunoperoxidase and indirect immunofluorescent techniques. Antibodies were directed against antigenic markers, the expressions of which overlapped in time: GD3 ganglioside in immature neuroectodermal cells; vimentin in radial glia; glial fibrillary acidic protein (GFAP) in astrocytes; and carbonic anhydrase (CA) and galactocerebroside (GC) in oligodendrocytes. A histochemical stain for iron was also used as a marker of oligodendrocytes. Small cells of the subventricular zone (SVZ) were stained with anti-GD3 but not with the other antibodies. By 16 d of gestation (E16), the SVZ generated large, round cells and thick, process-bearing cells that were GD3+/CA+/iron+. These cells then appeared in the cingulum and, with time, increased in numbers and extended thick processes as they filled the subcortical white matter. These cells eventually lost their reactivity to anti-GD3 but became GC+/CA+ with processes extending to myelin sheaths. At E15 radial glia were stained with the anti-vimentin antibody but were negative for GFAP. At birth, only the vimentin+ radial glia midline between the 2 ventricles were GFAP+, but with time more vimentin+ cells became GFAP+. By 7 d of postnatal age all the vimentin+ cells were GFAP+ and had converged predominately on the cingulum. With time these cells condensed and took on characteristic shapes of astrocytes. The embryonic separation of the oligodendrocyte and the astrocyte lineage is supported by four pieces of evidence: (1) GD3+ cells were double labeled with anti-CA, and then went on to become GC+; (2) vimentin+ and GFAP+ cells were not also GD3+; (3) ultrastructural localization of anti-GD3 was confined to cells with characteristics consistent with developing oligodendrocytes; and (4) the shapes of GD3+, CA+, GC+, or iron+ cells did not resemble those of the vimentin+ or GFAP+ cells.

Animals↗

PubMed1981

The hematogenous origin of osteoclasts: experimental evidence from osteopetrotic (microphthalmic) mice treated with spleen cells from beige mouse donors.

The excessive skeletal mass and reduced bone resorption characteristic of osteopetrosis in microphthalmic (mi) mice can be corrected by irradiation and transfer of spleen cells from a normal littermate. Osteoclasts in beige (bg) mice, a mutation without osteopetrosis, have giant lysosomal granules. These two facts were exploited to trace osteoclast lineage. Microphthalmic mice treated with whole-body irradiation and spleen cells from a beige donor resorbed the excessive skeletal mass and recovered from osteopetrosis. Furthermore, osteoclasts in treated mi mice had giant lysosomal granules and resembled those found in bg donors when examined by light and transmission electron microscopy. These data provide direct evidence for a hematogenous origin of osteoclasts in mammals.

Animals↗

PubMed2004

Transgenic expression of Cre recombinase from the tyrosine hydroxylase locus.

Catecholaminergic neurons are affected in several neurological and psychiatric diseases. Tyrosine hydroxylase (TH) is the first, rate-limiting enzyme in catecholamine synthesis. We report a knockin mouse expressing Cre-recombinase from the 3'-untranslated region of the endogenous Th gene by means of an internal ribosomal entry sequence (IRES). The resulting Cre expression matches the normal pattern of TH expression, while the pattern and level of TH are not altered in the knockin mouse. Crossings with two different LacZ reporter mice demonstrated Cre-mediated genomic recombination in TH expressing tissues. In addition, LacZ was found in some unexpected cell populations (including oocytes), indicating recombination due to transient developmental TH expression. Our novel knockin mouse can be used for generation of tissue-specific or general knockouts (depending on scheme of crossing) in mice carrying genes flanked by loxP sites. This knockin mouse can also be used for tracing cell lineages expressing TH during development.

3' Untranslated Regions↗

PubMed2005

Unbiased contribution of the first two blastomeres to mouse blastocyst development.

Several recent studies have proposed a model that the organization of the mouse blastocyst is determined by the pattern of early cleavages: the plane of first cleavage divides the two-cell embryo into embryonic (Em) and abembryonic (Ab) halves, while the timing of the second cleavages specifies which blastomere becomes the Em half. This model is still controversial because of conflicting observations in various studies. Here, we investigated the possibility that the difference between mouse strains contributed to the discrepancy of the findings of different experiments regarding the relationship between the first two cleavages and the blastocyst axial pattern. First, we showed by using a lipophilic, fluorescent tracer that the plane of the first cleavage bears no consistent spatial relationship to the Em-Ab axis of the blastocyst regardless of the genotypic background. Secondly, the order of the second cleavage does not correlate with the Em-Ab polarity of the blastocyst. This was demonstrated by tracing the lineage of the early- and later-dividing two-cell stage blastomeres in the whole embryo as well as by comparing the developmental potential of isolated early- and later-dividing blastomeres and chimeras made entirely of early- or later-dividing blastomeres. These results suggest that contrary to recent studies, the differences between the early- and later-dividing blastomeres of the two-cell embryo are not functionally evident and do not define the Em-Ab polarity of the blastocyst. The significance of these findings is discussed in relation to human assisted reproduction and preimplantation genetic diagnosis.

Animals↗

PubMed1987

Cell surface antigens on human marrow cells: dissection of hematopoietic development using monoclonal antibodies and multiparameter flow cytometry.

A single sample of bone marrow includes the entire range of the developmental process, since cells of all stages and lineages are present. By selecting appropriate monoclonal antibodies, marrow cells of different lineages can be identified, even in their immature forms. Maturationally different bone marrow cells can be distinguished on the basis of their cell surface antigen expression and physical characteristics on a flow cytometer. Antigenic markers can be used within a lineage to trace the development from colony-forming cells to functional blood cells. Changes in cellular markers are observed as smooth, quantitative increases or decreases in cellular antigen expression. After defining the composition of normal marrow, it is possible to identify perturbations from the steady state and to monitor the return to homeostasis. Cells at various stages can be enumerated, then isolated for further study. In particular, these studies provide for the identification, purification and manipulation of the earliest hematopoietic progenitor cells.

Antibodies, Monoclonal↗

PubMed2002

Cellular dispersion patterns and phenotypes in the developing mouse superior colliculus.

The mammalian superior colliculus is structurally and functionally divided into two entities: superficial visual and deep multimodal motor. To discover the role, if any, of developmental processes in establishing separate tectal compartments, we have used highly unbalanced mouse chimaeras to mark cell dispersion pathways and trace cell lineages. Two forms of cell dispersion were detected: radial and tangential. Neither radial nor tangential forms of cell dispersion were found to exist on their own in any group of labeled cells. Radial cell dispersion was the predominant form of cell movement from the germinal zones and primarily associated with the differentiation of glutamatergic neurons. In contrast, tangential cell dispersion involved a minority of tectal cells, concentrated chiefly in the superficial layers and often associated with the upper aspects of radial columns. More scattered cells expressed gamma-aminobutyric acid (GABA) compared to columnar cells. Taken together, these results indicate separate developmental constraints for the development of glutamatergic and GABAergic neurons in the superior colliculus.

Animals↗

PubMed1983

Ontogeny and immunocytochemical differentiation of the pituitary gland in a sea turtle, Caretta caretta.

In the sea turtle Caretta caretta the dorsal wall of the pituitary anlage and the apex of the hypophyseal angle are derived from stomodeal epithelium adherent to the neural epithelium of the diencephalon; a substantial part of the ventral wall of the anlage is derived from epithelium of mixed origin (stomodeum and foregut). Distribution of immunoreactive cells in the embryonic gland suggests that pituitary peptide hormones (adrenocorticotropin, ACTH; melanotropin, MSH; prolactin, PRL; growth hormone, GH) are synthesized in cells from the dorsal wall, while cells producing glycoprotein hormones (luteinizing hormone, LH; thyrotropin, TSH) trace their lineage to ventral and ventrolateral areas of the anlage that include some endoderm. Mesenchymal movements mold the epithelial anlage in two steps, delineating first the posterior and subsequently the anterior area of the gland. During the former process the lateral lobes are defined, and material immunoreactive with antiserum to ACTH appears in epithelial cells of presumptive pars distalis (PD) and pars intermedia (PI). Delineation of the anterior end of the pituitary gland occurs as the hypophyseal stalk forms, approximately one-fourth through ontogenesis. Shortly thereafter, immunoreactions demonstrate synthetic activity of distinctively distributed cells containing ACTH, PRL, GH, LH and TSH. In Caretta the lateral lobes of the pituitary anlage give rise to a distinct layer of tissue around the PD (pars tuberalis interna, PTint) and a thick layer on the floor of the hypothalamus (juxtaneural pars tuberalis, juxPT). In the pituitaries of late embryos, juxPT tissue proximal to the PD contains many cells immunoreactive with LH antiserum; whereas cells in distal areas of the juxPT do not react with any antisera tested. LH-cells also occur in large numbers in the PTint and in the posterior PD where tissues of the partes tuberalis and distalis are continuous. Cells reactive with antiserum to TSH are found in small numbers in the PTint, and in larger numbers along with the LH-cells in the posterior PD. PRL-cells occur in the anterior PD, GH-cells in the posterior. ACTH-cells are found primarily in the anterior two-thirds of the PD.

Animals↗

PubMed2001

Y chromosome compound haplotypes with the microsatellite markers DXYS265, DXYS266, and DXYS241.

Two newly developed microsatellite markers on Yp11 (DXYS265) and Yq11.21 (DXYS266) and our previously reported marker, on Yp11 (DXYS241), were typed by triplex polymerase chain reaction (PCR) in 102 Japanese, 18 white American, and 17 black American males. The DXYS265 locus revealed three alleles, the DXYS266 locus showed two alleles, while the DXYS241 locus showed five alleles. Nine different compound haplotypes were observed among the males. Of these, two haplotypes were common to all groups, while four were limited to Japanese. Pedigree analysis of 61 Japanese families revealed no mutations of these loci. The triplex PCR developed in this study, as well as the new loci, are useful for tracing paternal lineages in human migration studies and population analysis, in addition to Y chromosome evolutionary studies.

Alleles↗

PubMed1992

Replication-defective virus infection of feather buds produces a localized region of beta-galactosidase activity.

We are interested in using retroviral vectors to trace cell lineage and to introduce exogenous genes in chicken skin explant cultures. Here the LZ10 virus carrying the gene encoding beta-galactosidase was introduced to the skin explants by two different means: a) the virus was added to the media or b) the virus was microinjected into regions of the developing feather buds. Infection by microinjection led to localized expression of beta-galactosidase in the developing feather bud, while, surprisingly, infection by adding the virus to the culture media led to localized band of beta-galactosidase expression in the middle of the feather filament. The significance of this finding in skin morphogenesis and as a tool for experimental embryology is discussed.

Animals↗

PubMed1994

Heterogeneous (positional) expression of hepatic glutamine synthetase: features, regulation and implications for hepatocarcinogenesis.

Glutamine synthetase expression in liver parenchyma is restricted to a small population of pericentral hepatocytes surrounding the central veins. Studies on the development of this heterogeneous (positional) gene expression and of the changes observed in response to experimental alterations of liver physiology or manipulations of hepatocytes in culture have revealed that it is dependent on cell-cell and cell-matrix interactions rather than on the levels of hormones and other modulating factors. The considerable stability of GS expression may point to further events leading to a defined differentiated GS+ phenotype. Observations during experimental hepatocarcinogenesis indicate that strong GS expression may be used for tracing hepatocellular lineages during preneoplastic and early neoplastic stages. Furthermore, these studies suggest a relationship between the GS+ phenotype and enhanced growth of these lesions. Future studies should help to define the diagnostic value of GS and its significance for new chemotherapeutic strategies.

Adipose Tissue↗

PubMed1989

The determination of neuronal fate in the cerebral cortex.

During the embryonic development of the cerebral cortex, young neurons migrate out into characteristic laminar positions and form specific axonal connections with other neurons. The birthdate of a neuron, and its tangential location in the ventricular zone, can serve as markers that predict its normal laminar fate and pattern of connectivity. In order to test whether cells of the developing cerebral cortex are committed to their normal fates, several types of transplantation experiment have challenged young cortical neurons to alter their identities or connections in novel environments. Other recent experiments have employed retroviral vectors to trace neuronal lineages in the cortex. Together, these studies suggest that phenotypic commitment involves a series of decisions. Certain developmental restrictions--for example, commitment to a laminar identity--may occur at or around the time of the cell's final mitotic division, whereas the refinement of area-specific axonal projections occurs as the neuron differentiates within the cortex.

Animals↗

PubMed1994

Early CNS development: distal-less related genes and forebrain development.

The ever increasing number of molecular markers available for the study of developing structures is revolutionizing developmental neurobiology. It is now possible to identify entirely new groups of cells and trace their lineages among all other cell populations. Recent studies on the expression domains of a variety of genes specifically expressed in the developing CNS are beginning to give us a better understanding of the early regionalization of the CNS and, in particular, of the forebrain.

Amino Acid Sequence↗

PubMed2025

Combined somatic mutation and transcriptome analysis reveals region-specific differences in clonal architecture in human cortex.

The human cerebral cortex is specialized into regions, but little is known about how human cellular lineages shape cortical regional variation and neuronal cell-type distribution during development. Here, we map single-cell lineages of human cortical regions and neuronal subtypes using >1,000 somatic single-nucleotide variants (sSNVs) identified from deep bulk whole-genome sequencing and analyzed over 25 regions and >72,000 single cells. In the fronto-parietal cortex, sSNVs are rarely restricted, marking neuron-generating clones that disperse into neighboring regions. In contrast, the primary visual cortex harbors 30%-70% more sSNVs than the neighboring secondary visual cortex. Clones at this border exhibit more restricted dispersion, suggesting late developmental lineage segregation. Single-nucleus sSNV and whole-transcriptome analysis reveal glutamatergic neuron clones with modest regional restrictions that share low-mosaic sSNVs with some GABAergic neurons, suggesting a recent dorsal cortical progenitor. Our analysis reveals human-specific cortical lineage patterns, regional differences in clonal patterns, and late divergence of some glutamatergic/GABAergic lineages.

Humans↗

PubMed2025

Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.

Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.

Animals↗

PubMed2024

Synthetic DNA barcodes identify singlets in scRNA-seq datasets and evaluate doublet algorithms.

Single-cell RNA sequencing (scRNA-seq) datasets contain true single cells, or singlets, in addition to cells that coalesce during the protocol, or doublets. Identifying singlets with high fidelity in scRNA-seq is necessary to avoid false negative and false positive discoveries. Although several methodologies have been proposed, they are typically tested on highly heterogeneous datasets and lack a priori knowledge of true singlets. Here, we leveraged datasets with synthetically introduced DNA barcodes for a hitherto unexplored application: to extract ground-truth singlets. We demonstrated the feasibility of our framework, "singletCode," to evaluate existing doublet detection methods across a range of contexts. We also leveraged our ground-truth singlets to train a proof-of-concept machine learning classifier, which outperformed other doublet detection algorithms. Our integrative framework can identify ground-truth singlets and enable robust doublet detection in non-barcoded datasets.

Algorithms↗