Cell lineage specification during development of the anterior lateral plate mesoderm and forelimb field

The lateral plate mesoderm (LPM) is a transient embryonic tissue that gives rise to a diverse range of mature cell types, including the cardiovascular system, the urogenital system, endoskeleton of the limbs, and mesenchyme of the gut. While the genetic processes that drive development of these tissues are well defined, the early cell fate choices underlying LPM development and specification are poorly understood. In this study, we utilize single-cell transcriptomics to define cell lineage specification during development of the anterior LPM and the forelimb field in the chicken embryo. We identify the molecular pathways directing differentiation of the aLPM towards a somatic or splanchnic cell fate, and subsequent emergence of the forelimb mesenchyme. We establish the first transcriptional atlas of progenitor, transitional and mature cell types throughout the early forelimb field and uncover the global signalling pathways which are active during LPM differentiation and forelimb initiation. Specification of the somatic and splanchnic LPM from undifferentiated mesoderm utilizes distinct signalling pathways and involves shared repression of early mesodermal markers, followed by activation of lineage-specific gene modules. We identify rapid activation of the transcription factor TWIST1 in the somatic LPM preceding activation of known limb initiation genes, such as TBX5, which plays a likely role in epithelial-to-mesenchyme transition of the limb bud mesenchyme. Furthermore, development of the somatic LPM and limb is dependent on ectodermal BMP signalling, where BMP antagonism reduces expression of key somatic LPM and limb genes to inhibit formation of the limb bud mesenchyme. Together, these findings provide new insights into molecular mechanisms that drive fate cell choices during specification of the aLPM and forelimb initiation.

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Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22189667 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9667

Author(s):

Geoffrey Brown

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Cell Lineage ◽

Cell Types ◽

Mature Cell ◽

Cellular Gene ◽

Hematopoietic Stem ◽

Homeostatic Process ◽

Epigenetic Events

In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.

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Direct Reprogramming of Non-limb Fibroblasts to Cells with Properties of Limb Progenitors

10.1101/2021.10.01.462632 ◽

2021 ◽

Author(s):

Yuji Atsuta ◽

Changhee Lee ◽

Alan R. Rodrigues ◽

Charlotte Colle ◽

Reiko R. Tomizawa ◽

...

Keyword(s):

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Types ◽

Limb Bud ◽

Lateral Plate Mesoderm ◽

Direct Reprogramming ◽

Key Factors ◽

Lateral Plate ◽

Mesenchymal Progenitors ◽

Similar Gene

SUMMARYThe early limb bud consists of mesenchymal progenitors (limb progenitors) derived from the lateral plate mesoderm (LPM) that produce most of the tissues of the mature limb bud. The LPM also gives rise to the mesodermal components of the trunk, flank and neck. However, the mesenchymal cells generated at these other axial levels cannot produce the variety of cell types found in the limb bud, nor can they be directed to form a patterned appendage-like structure, even when placed in the context of the signals responsible for organizing the limb bud. Here, by taking advantage of a direct reprogramming approach, we find a set of factors (Prdm16, Zbtb16, and Lin28) normally expressed in the early limb bud, that are capable of imparting limb progenitor-like properties to non-limb fibroblasts. Cells reprogrammed by these factors show similar gene expression profiles, and can differentiate into similar cell types, as endogenous limb progenitors. The further addition of Lin41 potentiates proliferation of the reprogrammed cells while suppressing differentiation. These results suggest that these same four key factors may play pivotal roles in the specification of endogenous limb progenitors.

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Anterior pituitary cells defective in the cell-autonomous factor, df, undergo cell lineage specification but not expansion

Development ◽

10.1242/dev.122.1.151 ◽

1996 ◽

Vol 122 (1) ◽

pp. 151-160 ◽

Cited By ~ 4

Author(s):

P.J. Gage ◽

M.L. Roller ◽

T.L. Saunders ◽

L.M. Scarlett ◽

S.A. Camper

Keyword(s):

Anterior Pituitary ◽

Cell Lineage ◽

Cell Types ◽

Limited Commitment ◽

Recessive Mutation ◽

Pituitary Cells ◽

Lineage Specification ◽

Ames Dwarf ◽

Dependent Cell ◽

A Cell

The Ames dwarf mouse transmits a recessive mutation (df) resulting in a profound anterior pituitary hypocellularity due to a general lack of thyrotropes, somatotropes and lactotropes. These cell types are also dependent on the pituitary-specific transcription factor, Pit-1. We present evidence that expression of Pit-1 and limited commitment to these cells lineages occurs in df/df pituitaries. Thus, the crucial role of df may be in lineage-specific proliferation, rather than cytodifferentiation. The presence of all three Pit-1-dependent cell types in clonally derived clusters provides compelling evidence that these three lineages share a common, pluripotent precursor cell. Clusters containing different combinations of Pit-1-dependent cell types suggests that the Pit-1+ precursor cells choose from multiple developmental options during ontogeny. Characterization of df/df<-->+/+ chimeric mice demonstrated that df functions by a cell-autonomous mechanism. Therefore, df and Pit-1 are both cell-autonomous factors required for thyrotrope, somatotrope and lactotrope ontogeny, but their relative roles are different.

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Pannexin 1 influences lineage specification of human iPSCs

10.1101/2021.01.21.427632 ◽

2021 ◽

Author(s):

Rebecca J. Noort ◽

Grace A. Christopher ◽

Jessica L. Esseltine

Keyword(s):

Cell Fate ◽

Cell Communication ◽

Cell Lineage ◽

The Body ◽

Human Embryos ◽

Lineage Specification ◽

Cell Stage ◽

Cell Fate Decisions ◽

Pannexin 1 ◽

Human Ipscs

AbstractEvery single cell in the body communicates with nearby cells to locally organize activities with their neighbors and dysfunctional cell-cell communication can be detrimental during cell lineage commitment, tissue patterning and organ development. Pannexin channels (PANX1, PANX2, PANX3) facilitate purinergic paracrine signaling through the passage of messenger molecules out of cells. PANX1 is widely expressed throughout the body and has recently been identified in human oocytes as well as 2 and 4-cell stage human embryos. Given its abundance across multiple adult tissues and its expression at the earliest stages of human development, we sought to understand whether PANX1 impacts human induced pluripotent stem cells (iPSCs) or plays a role in cell fate decisions. Western blot, immunofluorescence and flow cytometry reveal that PANX1 is expressed in iPSCs as well as all three germ lineages derived from these cells: ectoderm, endoderm, and mesoderm. PANX1 demonstrates differential glycosylation patterns and subcellular localization across the germ lineages. Using CRISPR-Cas9 gene ablation, we find that loss of PANX1 has no obvious impact on iPSC morphology, survival, or pluripotency gene expression. However, PANX1 knockout iPSCs exhibit apparent lineage specification bias during 2-dimensional and 3-dimensional spontaneous differentiation into the three germ lineages. Indeed, loss of PANX1 significantly decreases the proportion of ectodermal cells within spontaneously differentiated cultures, while endodermal and mesodermal representation is increased in PANX1 knockout cells. Importantly, PANX1 knockout iPSCs are fully capable of differentiating toward each specific lineage when exposed to the appropriate external signaling pressures, suggesting that although PANX1 influences germ lineage specification, it is not essential to this process.Graphical abstract

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The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor

Development ◽

10.1242/dev.124.11.2235 ◽

1997 ◽

Vol 124 (11) ◽

pp. 2235-2244 ◽

Cited By ~ 67

Author(s):

H. Ohuchi ◽

T. Nakagawa ◽

A. Yamamoto ◽

A. Araga ◽

T. Ohata ◽

...

Keyword(s):

Sonic Hedgehog ◽

Limb Bud ◽

Fibroblast Growth ◽

Lateral Plate Mesoderm ◽

Lateral Plate ◽

Bud Formation ◽

Limb Mesenchyme ◽

Vertebrate Limb ◽

Fgf10 Expression ◽

Zone Of Polarizing Activity

Vertebrate limb formation has been known to be initiated by a factor(s) secreted from the lateral plate mesoderm. In this report, we provide evidence that a member of the fibroblast growth factor (FGF) family, FGF10, emanates from the prospective limb mesoderm to serve as an endogenous initiator for limb bud formation. Fgf10 expression in the prospective limb mesenchyme precedes Fgf8 expression in the nascent apical ectoderm. Ectopic application of FGF10 to the chick embryonic flank can induce Fgf8 expression in the adjacent ectoderm, resulting in the formation of an additional complete limb. Expression of Fgf10 persists in the mesenchyme of the established limb bud and appears to interact with Fgf8 in the apical ectoderm and Sonic hedgehog in the zone of polarizing activity. These results suggest that FGF10 is a key mesenchymal factor involved in the initial budding as well as the continuous outgrowth of vertebrate limbs.

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Cell autonomous functions of the receptor tyrosine kinase TIE in a late phase of angiogenic capillary growth and endothelial cell survival during murine development

Development ◽

10.1242/dev.122.10.3013 ◽

1996 ◽

Vol 122 (10) ◽

pp. 3013-3021 ◽

Cited By ~ 2

Author(s):

J. Partanen ◽

M.C. Puri ◽

L. Schwartz ◽

K.D. Fischer ◽

A. Bernstein ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Late Phase ◽

Cell Lineage ◽

Cell Types ◽

Limb Bud ◽

Cell Populations ◽

Cell Integrity

TIE is a receptor tyrosine kinase expressed in both mature endothelial cells and their precursors, as well as in some hematopoietic cells. Mouse embryos homozygous for a disrupted Tie allele die at midgestation due to impaired endothelial cell integrity and resulting hemorrhage. Here we have performed chimeric analysis to study further the function of the murine TIE in the development of embryonic vasculature and in the hematopoietic system. Cells lacking a functional Tie gene (tie(lcz)/tie(lczn-) cells) contributed to the embryonic vasculature at E10.5 as efficiently as cells heterozygous for a targeted Tie allele (tie(lcz)/+ cells). Thus, TIE does not play a significant role in vasculogenesis or in early angiogenic processes, such as formation of the intersomitic arteries and limb bud vascularization. At E15.5 tie(lcz)/tie(lczn-) cells still readily contributed to major blood vessels and to endothelial cells of organs such as lung and heart, which have been suggested to be vascularized by angioblast differentiation. In contrast, the tie(lcz)/tie(lczn-) cells were selected against in the capillary plexuses of several angiogenically vascularized tissues, such as brain and kidney. Our results thus support a role for TIE in late phases of angiogenesis but not vasculogenesis. Furthermore, the results suggest that different mechanisms regulate early and late angiogenesis and provide support for a model of differential organ vascularization by vasculogenic or angiogenic processes. Analysis of adult chimeras suggested that TIE is required to support the survival or proliferation of certain types of endothelial cells demonstrating heterogeneity in the growth/survival factor requirements in various endothelial cell populations. Chimeric analysis of adult hematopoietic cell populations, including peripheral platelets and bone marrow progenitor cells, revealed that tie(lcz)/tie(lczn-) cells were able to contribute to these cell types in a way indistinguishable from tie(lcz)/+ or wild-type cells. Thus, the primary function of TIE appears to be restricted to the endothelial cell lineage.

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Modifications of cell fate specification in equal-cleaving nemertean embryos: alternate patterns of spiralian development

Development ◽

10.1242/dev.121.10.3175 ◽

1995 ◽

Vol 121 (10) ◽

pp. 3175-3185 ◽

Cited By ~ 1

Author(s):

M.Q. Martindale ◽

J.Q. Henry

Keyword(s):

Cell Fate ◽

Cell Lineage ◽

Cell Types ◽

Embryonic Cell ◽

Specific Cell ◽

Cell Fate Specification ◽

Cell Fates ◽

Developmental Potential ◽

Fate Specification ◽

Symmetry Properties

The nemerteans belong to a phylum of coelomate worms that display a highly conserved pattern of cell divisions referred to as spiral cleavage. It has recently been shown that the fates of the four embryonic cell quadrants in two species of nemerteans are not homologous to those in other spiralian embryos, such as the annelids and molluscs (Henry, J. Q. and Martindale, M. Q. (1994a) Develop. Genetics 15, 64–78). Equal-cleaving molluscs utilize inductive interactions to establish quadrant-specific cell fates and embryonic symmetry properties following fifth cleavage. In order to elucidate the manner in which cell fates are established in nemertean embryos, we have conducted cell isolation and deletion experiments to examine the developmental potential of the early cleavage blastomeres of two equal-cleaving nemerteans, Nemertopsis bivittata and Cerebratulus lacteus. These two species display different modes of development: N. bivittata develops directly via a non-feeding larvae, while C. lacteus develops to form a feeding pilidium larva which undergoes a radical metamorphosis to give rise to the juvenile worm. By examining the development of certain structures and cell types characteristic of quadrant-specific fates for each of these species, we have shown that isolated blastomeres of the indirect-developing nemertean, C. lacteus, are capable of generating cell fates that are not a consequence of that cell's normal developmental program. For instance, dorsal blastomeres can form muscle fibers when cultured in isolation. In contrast, isolated blastomeres of the direct-developing species, N. bivittata do not regulate their development to the same extent. Some cell fates are specified in a precocious manner in this species, such as those that give rise to the eyes. Thus, these findings indicate that equal-cleaving spiralian embryos can utilize different mechanisms of cell fate and axis specification. The implications of these patterns of nemertean development are discussed in relation to experimental work in other spiralian embryos, and a model is presented that accounts for possible evolutionary changes in cell lineage and the process of cell fate specification amongst these protostome phyla.

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Lineage Decision-Making within Normal Haematopoietic and Leukemic Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21062247 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2247

Author(s):

Geoffrey Brown ◽

Lucía Sánchez ◽

Isidro Sánchez-García

Keyword(s):

Stem Cells ◽

Cell Fate ◽

Immune Cell ◽

Alternative Pathway ◽

Cell Lineage ◽

Cell Types ◽

Haematopoietic Stem Cell ◽

Haematopoietic Stem Cells ◽

Wide Range ◽

Lineage Decision

To produce the wide range of blood and immune cell types, haematopoietic stem cells can “choose” directly from the entire spectrum of blood cell fate-options. Affiliation to a single cell lineage can occur at the level of the haematopoietic stem cell and these cells are therefore a mixture of some pluripotent cells and many cells with lineage signatures. Even so, haematopoietic stem cells and their progeny that have chosen a particular fate can still “change their mind” and adopt a different developmental pathway. Many of the leukaemias arise in haematopoietic stem cells with the bulk of the often partially differentiated leukaemia cells belonging to just one cell type. We argue that the reason for this is that an oncogenic insult to the genome “hard wires” leukaemia stem cells, either through development or at some stage, to one cell lineage. Unlike normal haematopoietic stem cells, oncogene-transformed leukaemia stem cells and their progeny are unable to adopt an alternative pathway.

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Maintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor–Ligand Interactions

Journal of Experimental Medicine ◽

10.1084/jem.20040394 ◽

2004 ◽

Vol 200 (4) ◽

pp. 469-479 ◽

Cited By ~ 236

Author(s):

Thomas M. Schmitt ◽

Maria Ciofani ◽

Howard T. Petrie ◽

Juan Carlos Zúñiga-Pflücker

Keyword(s):

T Cell ◽

Notch Signaling ◽

Cell Fate ◽

Stromal Cells ◽

Cell Lineage ◽

Notch Receptor ◽

Lineage Specification ◽

Cell Specification ◽

Receptor Ligand ◽

Ligand Interactions

Notch signaling has been shown to play a pivotal role in inducing T lineage commitment. However, T cell progenitors are known to retain other lineage potential long after the first point at which Notch signaling is required. Thus, additional requirements for Notch signals and the timing of these events relative to intrathymic differentiation remain unknown. Here, we address this issue by culturing subsets of CD4 CD8 double negative (DN) thymocytes on control stromal cells or stromal cells expressing Delta-like 1 (Dll1). All DN subsets were found to require Notch signals to differentiate into CD4+ CD8+ T cells. Using clonal analyses, we show that CD44+ CD25+ (DN2) cells, which appeared committed to the T cell lineage when cultured on Dll1-expressing stromal cells, nonetheless gave rise to natural killer cells with a progenitor frequency similar to that of CD44+ CD25− (DN1) thymocytes when Notch signaling was absent. These data, together with the observation that Dll1 is expressed on stromal cells throughout the thymic cortex, indicates that Notch receptor–ligand interactions are necessary for induction and maintenance of T cell lineage specification at both the DN1 and DN2 stages of T cell development, suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T lineage.

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Expression of (beta)-catenin in the developing chick myotome is regulated by myogenic signals

Development ◽

10.1242/dev.127.19.4105 ◽

2000 ◽

Vol 127 (19) ◽

pp. 4105-4113

Author(s):

M. Schmidt ◽

M. Tanaka ◽

A. Munsterberg

Keyword(s):

Gene Expression ◽

Wnt Pathway ◽

Molecular Mechanisms ◽

Signalling Pathways ◽

Specific Gene ◽

Beta Catenin ◽

Lateral Plate Mesoderm ◽

Lateral Plate ◽

Cell Specification ◽

Myogenic Precursor

The developmental signals that govern cell specification and differentiation in vertebrate somites are well understood. However, little is known about the downstream signalling pathways involved. We have shown previously that a combination of Shh protein and Wnt1 or Wnt3a-expressing fibroblasts is sufficient to activate skeletal muscle-specific gene expression in somite explants. Here, we have examined the molecular mechanisms by which the Wnt-mediated signal acts on myogenic precursor cells. We show that chick frizzled 1 (Fz1), beta-catenin and Lef1 are expressed during somitogenesis. Lef1 and beta-catenin transcripts become restricted to the developing myotome. Furthermore, beta-catenin is expressed prior to the time at which MyoD transcripts can be detected. Expression of beta-catenin mRNA is regulated by positive and negative signals derived from neural tube, notochord and lateral plate mesoderm. These signals include Bmp4, Shh and Wnt1/Wnt3a itself. In somite explants, Fz1, beta-catenin and Lef1 are expressed prior to activation of myogenesis in response to Shh and Wnt signals. Thus, our data show that a combination of Shh and Wnt1 upregulates expression of Wnt pathway components in developing somites prior to myogenesis. Thus, Wnt1 could act through beta-catenin on cells in the myotome.

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