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Biomedical subjects

Morag Robertson

Publications and source records attributed to Morag Robertson.

8 recordsLinked to original sources
PubMed2006

Nanog retrotransposed genes with functionally conserved open reading frames.

The Nanog gene plays a key role in the pluripotency of early embryonic cells in vitro and in vivo. In this article retrotransposed copies of Nanog, termed NanogPc and NanogPd, are identified on mouse Chromosomes 4 and 7, respectively. In contrast to the two previously characterized mouse Nanog retrogenes that contain multiple frameshifts and point mutations, NanogPc and NanogPd are 98% identical to NANOG within the open reading frame and encode proteins with activity in an embryonic stem cell self-renewal assay. Mutations common to all four retrotransposed genes but distinct from Nanog suggest divergence from a common progenitor that appears likely to be Nanog because transcripts derived from Nanog but not from the retrogenes are detected in germ-line cells. The possibility that expression of Nanog could be erroneously attributed to novel cellular sources is suggested by the high homology among Nanog, NanogPc, and NanogPd. Analysis of distinct Mus species suggests that NanogPc and NanogPd arose between divergence of M. caroli and M. spretus and indicates that Nanog retrotransposition events continue to occur at a high frequency, a property likely to extend to other germ-line transcripts.

Amino Acid Sequence↗
PubMed2003

Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.

Embryonic stem (ES) cells undergo extended proliferation while remaining poised for multilineage differentiation. A unique network of transcription factors may characterize self-renewal and simultaneously suppress differentiation. We applied expression cloning in mouse ES cells to isolate a self-renewal determinant. Nanog is a divergent homeodomain protein that directs propagation of undifferentiated ES cells. Nanog mRNA is present in pluripotent mouse and human cell lines, and absent from differentiated cells. In preimplantation embryos, Nanog is restricted to founder cells from which ES cells can be derived. Endogenous Nanog acts in parallel with cytokine stimulation of Stat3 to drive ES cell self-renewal. Elevated Nanog expression from transgene constructs is sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 levels. Cytokine dependence, multilineage differentiation, and embryo colonization capacity are fully restored upon transgene excision. These findings establish a central role for Nanog in the transcription factor hierarchy that defines ES cell identity.

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PubMed2003

Neutralizing tumor necrosis factor-alpha activity suppresses activation of infiltrating macrophages in experimental autoimmune uveoretinitis.

PURPOSE: During experimental autoimmune uveoretinitis (EAU), infiltrating macrophages become activated to express nitric oxide synthase (NOS)-2 and generate nitric oxide (NO). The current study was designed to determine whether neutralizing TNF activity with a soluble fusion protein of TNFp55 receptor (sTNFr-IgG) inhibits macrophage activation, thereby contributing to reduced tissue damage observed with such treatment. METHODS: EAU was induced in Lewis rats by active immunization with soluble retinal extract (RE) and pertussis toxin (intraperitoneally), and animals were treated on days 6 and 8 after immunization with either sTNFr-IgG or human (hu)IgG. Disease course and severity were noted clinically, and eyes were enucleated for histologic scoring, including TUNEL immunofluorescence, at various stages of disease. Infiltrating retinal macrophages were isolated through a density gradient and subsequently phenotyped by flow cytometry, analyzed for ability to produce nitrite, either spontaneously or after cytokine stimulation, and assayed by PCR for cytokine gene expression. RESULTS: Neutralizing TNF activity suppressed tissue damage without impeding myeloid cell infiltrate. Moreover, with sTNFr-IgG treatment, infiltrating macrophages demonstrated reduced nitrite production at the height of disease, and the level of apoptosis within the retina of both ED1(+) cells and resident cells was reduced. PCR analysis demonstrated a significant increase in TGF beta signal and absent or low TNF signal throughout the disease course after treatment with sTNFr-IgG. CONCLUSIONS: sTNFr-IgG successfully suppresses retinal damage and impairs macrophage activation but not trafficking during EAU. sTNFr-IgG-mediated suppression of NO production results in reduced levels of apoptosis of inflammatory cells and reduction in photoreceptor damage.

Animals↗
PubMed2003

Control of myeloid activity during retinal inflammation.

Combating myeloid cell-mediated destruction of the retina during inflammation or neurodegeneration is dependent on the integrity of homeostatic mechanisms within the tissue that may suppress T cell activation and their subsequent cytokine responses, modulate infiltrating macrophage activation, and facilitate healthy tissue repair. Success is dependent on response of the resident myeloid-cell populations [microglia (MG)] to activation signals, commonly cytokines, and the control of infiltrating macrophage activation during inflammation, both of which appear highly programmed in normal and inflamed retina. The evidence that tissue CD200 constitutively provides down-regulatory signals to myeloid-derived cells via cognate CD200-CD200 receptor (R) interaction supports inherent tissue control of myeloid cell activation. In the retina, there is extensive neuronal and endothelial expression of CD200. Retinal MG in CD200 knockout mice display normal morphology but unlike the wild-type mice, are present in increased numbers and express nitric oxide synthase 2, a macrophage activation marker, inferring that loss of CD200 or absent CD200R ligation results in "classical" activation of myeloid cells. Thus, when mice lack CD200, they show increased susceptibility to and accelerated onset of tissue-specific autoimmunity.

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