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Biomedical subjects

N Winston

Publications and source records attributed to N Winston.

6 recordsLinked to original sources
PubMed2001

Regulation of early embryo development: functional redundancy between cyclin subtypes.

Cellular proliferation during early embryo development is achieved by the serial cleavage of individual blastomeres into increasingly smaller cells, in the absence of cell growth. This simplified cell division process has facilitated the study of the cell cycle and its regulatory pathways. The cell cycle of mammalian cells is controlled by a number of mechanisms, including the activity of cyclin-dependent protein kinase complexes. Numerous cyclin proteins have been identified and these share structural and functional characteristics. For each of the A- and B-type cyclins, two subtypes have been identified so far in mammals. However, in both cases the two subtype genes are expressed differentially, suggesting that they might have specific roles. The requirement for individual cyclin A and B proteins during early mouse embryo development has been examined using gene-targeted deletion and immunofluorescence techniques. These studies have shown that cyclin A1 is not essential for early embryonic development and cyclin A2 only becomes essential for development beyond the stage of implantation. Cyclin B1 is also essential for development and its critical regulatory role during the meiotic maturation of mouse oocytes will be considered. This review will discuss the studies that have attempted to explain the possible redundancy between the different cyclin subtypes.

Animals↗
PubMed2001

tiK+ toK+: an embryonic clock?

During embryogenesis cells make appropriately timed developmental decisions. Both 'hourglass-like' and 'clock-like' mechanisms have been demonstrated to act as timers in early development. The cell cycle rhythm, using feedback circuits to drive cells unidirectionally through checkpoints, is an example of a clock-like timer, but how it operates to time developmental events is unclear. In other cell types, cyclic oscillations in K+ channel activity, which parallel cell cycle and circadian rhythms, may be part of the timing mechanism. Changes in K+ oscillations accompany key developmental transitions and oncogenic transformation. Channel blockade interferes pharmacologically with cell cycle initiation or progression, whereas channel over-expression can be oncogenic. K+ channel activity also exists in early mouse oocytes through to at least the blastocyst stage, and it oscillates in phase with the developmental cell cycles, being high in M/G1 and low in S/G2. It resembles physiologically the activity of the K+ channels of the eag- or erg-like families. Reverse transcriptase-polymerase chain reaction of mouse oocytes has revealed the presence of transcripts encoding both EAG- and ERG-like proteins throughout preimplantation development. Channel activity continues to oscillate with a cell cycle periodicity in embryos from which the nucleus has been removed, or after inhibition by puromycin of the cyclin B-cyclin-dependent kinase 1 driven component of the chromosomal cycle. Channel oscillatory activity thus appears to be able to function autonomously of the chromosomal cycle and may represent a distinct oscillatory timing activity with possible developmental significance.

Animals↗
PubMed2000

Early development of mouse embryos null mutant for the cyclin A2 gene occurs in the absence of maternally derived cyclin A2 gene products.

Progression through the mammalian cell cycle is regulated by the sequential activation and inactivation of the cyclin-dependent kinases. In adult cells, cyclin A2-dependent kinases are required for entry into S and M phases, completion of S phase, and centrosome duplication. However, mouse embryos lacking the cyclin A2 gene nonetheless complete preimplantation development, but die soon after implantation. In this report, we investigated whether a contribution of maternal cyclin A2 mRNA and protein to early embryonic cell cycles might explain these conflicting observations. Our data show that a maternal stock of cyclin A2 mRNA is present in the oocyte and persists after fertilization until the second mitotic cell cycle, when it is degraded to undetectable levels coincident with transcriptional activation of the zygotic genome. A portion of maternally derived cyclin A2 protein is stable during the first mitosis and persists in the cytoplasm, but is completely degraded at the second mitosis. The ability of cyclin A2-null mutants to develop normally from the four-cell to the postimplantation stage in the absence of detectable cyclin A2 gene product indicates therefore that cyclin A2 is dispensable for cellular progression during the preimplantation nongrowth period of mouse embryo development.

Amanitins↗
PubMed1991

Parthenogenetic activation and development of fresh and aged human oocytes.

OBJECTIVE: To develop a systematic study of the parthenogenetic activation and early development of human oocytes. DESIGN: Human oocytes (both freshly retrieved and remaining unfertilized after exposure to spermatozoa) were exposed to alcohol or calcium ionophore and examined for evidence of activation. SETTING: Academic research department of a teaching hospital. PATIENTS, PARTICIPANTS: Couples donating oocytes were undergoing therapy for infertility with in vitro fertilization or gamete intrafallopian transfer. INTERVENTIONS: Gonadotropin-releasing hormone agonist and human menopausal gonadotropin were administered at therapeutic doses. MAIN OUTCOME MEASURES: After application of activation stimuli at varying doses and durations, oocytes were examined for evidence of meiotic reactivation, pronuclear formation, deoxyribonucleic acid content, and cleavage. RESULTS: Fresh and aged human oocytes can be activated parthenogenetically using a calcium ionophore but at lower rates than seen for mouse oocytes (typically 50% to 60% versus 90% to 100%, respectively). Ethanol was a poor activating agent (maximum activation rate 16%). Human parthenotes can complete division to the eight cell stage. CONCLUSIONS: These results indicate that parthenote embryos may provide a source of material to study changes that occur during early human development. The data also raise the possibility that some early human pregnancy losses may involve oocytes that have been parthenogenetically activated spontaneously.

Calcimycin↗
PubMed1978

Chronic effects of methadone on a line tilt generalization gradient in the pigeon.

Using an adjusting interval schedule, pigeons were trained to key peck at a relatively constant rate during 45 degrees line tilt presentations and at an extremely low rate in the presence of 0 degrees and 90 degrees line angles. Subsequently, the birds received intramuscular injections of methadone hydrochloride every 8 hr in doses beginning at 3 mg/kg/day and increasing progressively to 90 mg/kg/day. Stimulus generalization tests were run on the first day and on the last day a given dose was administered to assess the development of tolerance. Although chronic methadone treatment was associated with an overall decrement in key peck rate, the gradients of line tilt generalization were indistinguishable from saline control gradients at doses as high as 90 mg/kg/day. Though the birds exhibited gross behavioral incoordination, visual stimulus control appeared unaffected.

Animals↗