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Vascular Mimicry:  interactions between trophoblast cells and maternal uterine vasculature in the placenta

vascular cast

In rodents and primates, conceptuses implant into the uterus and ensure their growth by promoting an increase in maternal blood flow to the placenta where nutrient and gas exchange occurs. They do this by promoting angiogenesis as well as dilation of maternal arteries. Trophoblast cells in the placenta also invade into the arteries creating a sinusoidal blood circuit in which maternal blood is in direct contact with the fetal trophoblast cells rather endothelial cell-lined vessels. Recent evidence has shown that some types of tumours in humans also have sinusoidal blood spaces. The goal of our research is to define the properties of the specialized trophoblast cells that line the maternal blood spaces, their developmental origins and factors that are critical for their development, using molecular and knockout mouse techniques.

Modes of cell and tissue growth during development with particular focus on polyploidy, cell hypertrophy and cell fusioncell cyclesTrophoblast giant cells in the placenta undergo rounds of DNA replication without intervening mitoses, a process called endoreduplication, and can accumulate DNA up to 1000C. The genome is ‘polytene’, a state in which many homologous chromatids are synapsed together resulting from multiple rounds of genome replication.  The functional importance of endoreduplication and polyploidy is a matter of speculation. Polyploid nuclei have been identified in many plant and animal cells with secretory or nutritive function such as salivary gland and follicle cells in Drosophila melanogaster, and leaf cells in plants. It has been suggested that polyploidy may increase their capacity for protein synthesis. Alternatively, it may be that endoreduplication and the associated cell hypertrophy allow tissue growth with less time and energy expenditure.

Cell lineage development and determinants of cell fate decision making during early development
cell lineage
The mouse has become a commonly used model for understanding the development and biology of the placenta, taking advantage of the ability to make transgenic mutant mice, culture trophoblast stem cells, analyse nutrient transport capacity, and the availability of dozens of cell subtype specific markers. We now have molecular insights into the development of all trophoblast cell types in the placenta: trophoblast stem cells; spongiotrophoblast, glycogen trophoblast cells parietal- and spiral artery-trophoblast giant cells in the junctional zone; two layers of syncytiotrophoblast as well as canal- and sinusoidal-giant cells in the labyrinth. We have focused our studies on identifying molecular mechanisms regulating the maintenance of multi-potent trophoblast stem cells as well as alternative fate specification of the various differentiated cell types in the mature placenta.

Maternal adaptations to pregnancy, with a particular interest in the role of the prolactin/placental lactogen-related hormone family

doppler

Maternal adaptations to pregnancy include dramatic changes in endocrine, immune, cardiovascular and metabolic systems. The Cross Lab is studying how hormones produced by the placenta regulate these changes and how such mechanisms may go awry during gestation to explain such adverse outcomes as fetal death, intrauterine growth restriction, and maternal diseases such as gestational diabetes and preeclampsia. Knockout mouse models are used in which differentiation of placental cells is affected or hormone genes are deleted, to examine the effects on fetal and maternal physiology. The student will perform breeding experiment to look at reproductive outcome also testing maternal cardiovascular and metabolic functions.

Developmental Plasticity and Trans-differentiation Potential of Amnion Cells

amnion pic

The amnion is a non-vascularized, thin, fluid-filled sac that surrounds the growing fetus during gestation. It is contiguous with the skin but the mechanisms underlying its development are poorly understood. In humans, some amnion cells express the Oct4 transcription factor that is otherwise only expressed in embryonic stem and germ cells. Our recent work has identified a molecular switch that establishes the boundary between skin and amnion tissue during early development. The goal of the ongoing project is to use molecular and cell biological approaches to test the developmental plasticity of amnion cells and potential therapeutic value.

Genetic and Environmental Determinants of Reproductive Success and Longevity

2 cows

Reproductive longevity, disease resistance, and structural soundness combine to determine the ability of cows to remain productive in the herd, a trait called “stayability”. It has a major economic impact because the costs of producing a replacement female are very high. Despite this, while other production traits in beef cattle such as weaning weight have improved dramatically through genetic selection in recent decades, there has been no gain, and potentially even a loss, in genetic merit for stayability based on beef breed association records. Research is exploring the biological, environmental, and management factors that may explain this.