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Dive into the research topics where Lynne Hartley is active.

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Featured researches published by Lynne Hartley.


Developmental Dynamics | 2004

Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human

Adam H. Hart; Lynne Hartley; Marilyn Ibrahim; Lorraine Robb

The murine Nanog gene, a member of the homeobox family of DNA binding transcription factors, has been shown recently to maintain pluripotency of embryonic stem cells. We have used a sequence homology and expression screen to identify and clone the mouse and human Nanog genes and characterized their phylogenetic context and expression patterns. We report here the gene structure and expression patterns of the mouse Nanog gene, the human Nanog and Nanog2 genes, and six processed human Nanog pseudogenes. Mouse Nanog expression is high in undifferentiated embryonic stem cells and is down‐regulated during embryonic stem cell differentiation, concomitant with loss of pluripotency. Murine embryonic Nanog expression is detected in the inner cell mass of the blastocyst. After implantation, Nanog is detectable at embryonic day (E) 6 in proximal epiblast in the region of the presumptive primitive streak. Expression extends distally as the streak elongates during gastrulation and remains restricted to epiblast. Nanog RNA is down‐regulated in cells ingressing through the streak to form mesoderm and definitive endoderm. Nanog expression also marks the pluripotent germ cells of the nascent gonad at E11.5–E12.5 and is highly expressed in germ cell tumour and teratoma‐derived cell lines. Reverse transcriptase‐polymerase chain reaction analysis detected mouse Nanog expression at low levels in several adult tissues. The human Nanog genes are expressed in embryonic stem cells and down‐regulated in all adult tissues and differentiated cell lines examined. High levels of human Nanog expression were detected by Northern analysis in the undifferentiated N‐Tera embryonal carcinoma cell line. The conservation in gene sequence, structure, and expression of mouse and human Nanog and Nanog2 genes may reflect a common role in the maintenance of pluripotency in both species. Developmental Dynamics 230:187–198, 2004.


Proceedings of the National Academy of Sciences of the United States of America | 2001

Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3

Andrew W. Roberts; Lorraine Robb; Steven Rakar; Lynne Hartley; Leonie A. Cluse; Nicos A. Nicola; Donald Metcalf; Douglas J. Hilton; Warren S. Alexander

Mice lacking suppressor of cytokine signaling 3 (SOCS3) exhibited embryonic lethality with death occurring between days 11 and 13 of gestation. At this stage, SOCS3−/− embryos were slightly smaller than wild type but appeared otherwise normal, and histological analysis failed to detect any anatomical abnormalities responsible for the lethal phenotype. Rather, in all SOCS3−/− embryos examined, defects were evident in placental development that would account for their developmental arrest and death. The placental spongiotrophoblast layer was significantly reduced and accompanied by increased numbers of giant trophoblast cells. Delayed branching of the chorioallantois was evident, and, although embryonic blood vessels were present in the labyrinthine layer of SOCS3−/− placentas, the network of embryonic vessels and maternal sinuses was poorly developed. Yolk sac erythropoiesis was normal, and, although the SOCS3−/− fetal liver was small at day 12.5 of gestation (E12.5), normal frequencies of erythroblasts and hematopoietic progenitor cells, including blast forming unit-erythroid (BFU-E) and, colony forming unit-erythroid (CFU-E) were present at both E11.5 and E12.5. Colony formation for both BFU-E and CFU-E from SOCS3−/− mice displayed wild-type quantitative responsiveness to erythropoietin (EPO), in the presence or absence of IL-3 or stem cell factor (SCF). These data suggest that SOCS3 is required for placental development but dispensable for normal hematopoiesis in the mouse embryo.


Immunity | 2004

SOCS3 Is a Critical Physiological Negative Regulator of G-CSF Signaling and Emergency Granulopoiesis

Ben A. Croker; Donald Metcalf; Lorraine Robb; Wei Wei; Sandra Mifsud; Ladina DiRago; Leonie A. Cluse; Kate D. Sutherland; Lynne Hartley; Emily Williams; Jian-Guo Zhang; Douglas J. Hilton; Nicos A. Nicola; Warren S. Alexander; Andrew W. Roberts

To determine the importance of suppressor of cytokine signaling-3 (SOCS3) in the regulation of hematopoietic growth factor signaling generally, and of G-CSF-induced cellular responses specifically, we created mice in which the Socs3 gene was deleted in all hematopoietic cells. Although normal until young adulthood, these mice then developed neutrophilia and a spectrum of inflammatory pathologies. When stimulated with G-CSF in vitro, SOCS3-deficient cells of the neutrophilic granulocyte lineage exhibited prolonged STAT3 activation and enhanced cellular responses to G-CSF, including an increase in cloning frequency, survival, and proliferative capacity. Consistent with the in vitro findings, mutant mice injected with G-CSF displayed enhanced neutrophilia, progenitor cell mobilization, and splenomegaly, but unexpectedly also developed inflammatory neutrophil infiltration into multiple tissues and consequent hind-leg paresis. We conclude that SOCS3 is a key negative regulator of G-CSF signaling in myeloid cells and that this is of particular significance during G-CSF-driven emergency granulopoiesis.


Cancer | 2005

The pluripotency homeobox gene NANOG is expressed in human germ cell tumors.

Adam H. Hart; Lynne Hartley; Karen Parker; Marilyn Ibrahim; Leendert H.J. Looijenga; Marija Pauchnik; Chung Wo Chow; Lorraine Robb

The NANOG gene, a member of the homeobox family of DNA binding transcription factors, was recently identified in a screen for pluripotency‐promoting genes. NANOG overexpression in murine embryonic stem cells is sufficient to maintain self‐renewal and to block differentiation. The NANOG gene is located on human chromosome 12p13, a region frequently duplicated in human tumors of germ cell origin and in cultured human embryonic stem cells. Here we investigate the expression and gene copy number of NANOG in human germ cells and tumors of germ cell origin.


Developmental Dynamics | 1998

epicardin: A novel basic helix-loop-helix transcription factor gene expressed in epicardium, branchial arch myoblasts, and mesenchyme of developing lung, gut, kidney, and gonads

Lorraine Robb; Lisa Mifsud; Lynne Hartley; Christine Biben; Neal G. Copeland; Debra J. Gilbert; Nancy A. Jenkins; Richard P. Harvey

We report the cloning, chromosomal localization, and analysis of the expression pattern of epicardin, a member of the basic helix‐loop‐helix (bHLH) family of transcription factors. Within its bHLH domain, the human and murine epicardin genes were most similar to paraxis, a bHLH gene important for segmentation of embryonic paraxial mesoderm. In situ hybridization studies revealed strong epicardin expression in murine embryos at 9.5 days postcoitum (dpc) in a region of the septum transversum at the base of the heart known as the proepicardial organ. This mesenchymal structure extends villous projections from which epicardial precursor cells emerge and migrate out over the surface of the myocardium. Strong expression was seen in individual migratory cells and clusters at 9.5 dpc and in a continuous epicardial cell layer in more mature hearts. Also from 9.5 dpc, epicardin transcripts were seen in endocardial cushions of the atrioventricular canal and outflow tract, in skeletal myoblasts within branchial arches and in condensing mesenchyme of gut, kidney, urinary tract, gonads, spleen, and lung. Northern analysis showed that expression persisted in mature visceral organs and heart, but was transient in skeletal muscle. The central role played by bHLH factors in pathways for tissue determination in the embryo suggests a function for epicardin in specification of select mesodermal cell populations associated with heart, cranial skeletal muscle, gut, and urogenital system. Dev. Dyn. 1998;213:105–113.


The Journal of Comparative Neurology | 2001

Development and reorganization of corticospinal projections in EphA4 deficient mice

Jason R. Coonan; Ursula Greferath; Jonathan Messenger; Lynne Hartley; Mark Murphy; Andrew W. Boyd; Mirella Dottori; Mary P. Galea; Perry F. Bartlett

The Eph family of receptor tyrosine kinases and their ligands, the ephrins, are important regulators of axon guidance and cell migration in the developing nervous system. Inactivation of the EphA4 gene results in axon guidance defects of the corticospinal tract, a major descending motor pathway that originates in the cortex and terminates at all levels of the spinal cord. In this investigation, we report that although the initial development of the corticospinal projection is normal through the cortex, internal capsule, cerebral peduncle, and medulla in the brain of EphA4 deficient animals, corticospinal axons exhibit gross abnormalities when they enter the gray matter of the spinal cord. Notably, many corticospinal axons fail to remain confined to one side of the spinal cord during development and instead, aberrantly project across the midline, terminating ipsilateral to their cells of origin. Given the possible repulsive interactions between EphA4 and one of its ligands, ephrinB3, this defect could be consistent with a loss of responsiveness by corticospinal axons to ephrinB3 that is expressed at the spinal cord midline. Furthermore, we show that EphA4 deficient animals exhibit ventral displacement of the mature corticospinal termination pattern, suggesting that developing corticospinal axons, which may also express ephrinB3, fail to be repelled from areas of high EphA4 expression in the intermediate zone of the normal spinal cord. Taken together, these results suggest that the dual expression of EphA4 on corticospinal axons and also within the surrounding gray matter is very important for the correct development and termination of the corticospinal projection within the spinal cord. J. Comp. Neurol. 436:248–262, 2001.


Developmental Dynamics | 2000

Cloning, expression analysis, and chromosomal localization of murine and human homologues of a Xenopus Mix gene

Lorraine Robb; Lynne Hartley; C. Glenn Begley; Thomas C. Brodnicki; Neal G. Copeland; Debra J. Gilbert; Nancy A. Jenkins; Andrew G. Elefanty

We report the cloning and chromosomal localization of murine and human Mix genes, members of a subclass of paired‐like homeobox genes of which the Xenopus laevis Mix.1 gene is the founding member. The murine Mix gene was mapped to the distal region of chromosome 1 and the human region to the syntenic region 1q41‐42. Northern analysis and RT‐PCR of murine adult and embryonic tissues demonstrated that Mix expression was restricted to the early embryo. Whole‐mount in situ hybridization revealed patchy but symmetrical Mix expression in visceral endoderm of embryonic day (E)5.5 embryos. In slightly older embryos, the expression was skewed to one side of the embryo and by E6.5, at the onset of gastrulation, expression was seen in the epiblast, visceral endoderm, nascent mesoderm, and the primitive streak. This expression pattern was maintained in mid‐ and late‐streak embryos. In early bud‐stage embryos, expression was strongest in the proximal two thirds of the streak, extending to the base of the allantois. By the headfold‐stage, expression was confined to the remnant of the primitive streak in the caudal region of the embryo and, after E8.0, in the caudal notochord and tail bud mesoderm. Mix transcripts were no longer detectable after embryonic day 9.5.


Current Biology | 1999

Suckling defect in mice lacking the soluble haemopoietin receptor NR6

Warren S. Alexander; Steven Rakar; Lorraine Robb; Alison Farley; Tracy A. Willson; Jian Guo Zhang; Lynne Hartley; Kikuchi Y; Kojima T; Nomura H; Hasegawa M; Maeda M; Louis Fabri; Jachno K; Andrew Nash; Donald Metcalf; Nicos A. Nicola; Douglas J. Hilton

Cytokines control a variety of cellular responses including proliferation, differentiation, survival and functional activation, via binding to specific receptors expressed on the surface of target cells [1]. The cytokine receptors of the haemopoietin family are defined by the presence of a conserved 200 amino acid extracellular domain known as the haemopoietin domain [2]. We report here the isolation of NR6, a haemopoietin receptor that, like the p40 subunit of interleukin-12 (IL-12) [3] and the EBI3 gene induced by Epstein-Barr virus infection in lymphocytes [4], contains a typical haemopoietin domain but lacks transmembrane and cytoplasmic domains. Although in situ hybridisation revealed NR6 expression at multiple sites in the developing embryo, mice lacking NR6 did not display obvious abnormalities and were born in the expected numbers. Neonatal NR6(-/-) mice failed to suckle, however, and died within 24 hours of birth, suggesting that NR6 is necessary for the recognition or processing of pheromonal signals or for the mechanics of suckling itself. In addition, NR6(-/-) mice had reduced numbers of haemopoietic progenitor cells, suggesting a potential role in the regulation of primitive haemopoiesis.


Circulation Research | 2010

Neuregulin 1 Sustains the Gene Regulatory Network in Both Trabecular and Nontrabecular Myocardium

Donna Lai; Xifu Liu; Ariel Forrai; Orit Wolstein; Jan Michalicek; Ishtiaq Ahmed; Alistair N. Garratt; Carmen Birchmeier; Mingdong Zhou; Lynne Hartley; Lorraine Robb; Michael P. Feneley; Diane Fatkin; Richard P. Harvey

Rationale: The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide. Objective: To understand the role of Nrg1 in heart development through analysis of null and hypomorphic Nrg1 mutant mice. Methods and Results: Chamber domains were correctly specified in Nrg1 mutants, although chamber-restricted genes Hand1 and Cited1 failed to be activated. The chamber GRN subsequently decayed with individual genes exhibiting decay patterns unrelated to known patterning boundaries. Both trabecular and nontrabecular myocardium were affected. Network demise was spatiotemporally dynamic, the most sensitive region being the central part of the left ventricle, in which the GRN underwent complete collapse. Other regions were partially affected with graded sensitivity. In vitro, Nrg1 promoted phospho-Erk1/2–dependent transcription factor expression, cardiomyocyte maturation and cell cycle inhibition. We monitored cardiac pErk1/2 in embryos and found that expression was Nrg1-dependent and levels correlated with cardiac GRN sensitivity in mutants. Conclusions: The chamber GRN is fundamentally labile and dependent on signaling from extracardiac sources. Nrg1–ErbB1/4–Erk1/2 signaling critically sustains elements of the GRN in trabecular and nontrabecular myocardium, challenging our understanding of Nrg1 function. Transcriptional decay patterns induced by reduced Nrg1 suggest a novel mechanism for cardiac transcriptional regulation and dysfunction in disease, potentially linking biomechanical feedback to molecular pathways for growth and differentiation.


Genesis | 2000

Targeted insertion of a lacZ reporter gene into the mouse Cer1 locus reveals complex and dynamic expression during embryogenesis.

Edouard G. Stanley; Christine Biben; Janette Allison; Lynne Hartley; Ian P. Wicks; Ian K. Campbell; Michael J. McKinley; Louise Barnett; Frank Koentgen; Lorraine Robb; Richard P. Harvey

Summary: The mouse Cer1 (mCer1, Cer‐l, Cerr1) gene encodes one member of a family of cytokines structurally and functionally related to the Xenopus head‐inducing factor, Cerberus (xCer). We generated a mouse line in which the Cer1 gene was inactivated by replacing the first coding exon with a lacZ reporter gene. Mice homozygous for this allele (Cer1lacZ) showed no apparent perturbation of embryogenesis or later development. However, the lacZ reporter revealed a number of hitherto uncharacterised sites of Cer1 expression in late fetal and adult tissues. Preliminary analysis suggests that Cer1 is not essential for their morphogenesis, differentiation, or homeostasis. genesis 26:259–264, 2000.

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Lorraine Robb

Walter and Eliza Hall Institute of Medical Research

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Richard P. Harvey

Victor Chang Cardiac Research Institute

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Warren S. Alexander

Walter and Eliza Hall Institute of Medical Research

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Clare L. Scott

Walter and Eliza Hall Institute of Medical Research

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Donald Metcalf

Walter and Eliza Hall Institute of Medical Research

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Mark Murphy

Walter and Eliza Hall Institute of Medical Research

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Mirella Dottori

Walter and Eliza Hall Institute of Medical Research

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Adam H. Hart

Walter and Eliza Hall Institute of Medical Research

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