Biomedical subjects

Suzanne Claxton

Publications and source records attributed to Suzanne Claxton.

4 recordsLinked to original sources

PubMed2006

Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells.

The neuroendocrine hypothalamus regulates a number of critical biological processes and underlies a range of diseases from growth failure to obesity. Although the elucidation of hypothalamic function has progressed well, knowledge of hypothalamic development is poor. In particular, little is known about the processes underlying the neurogenesis and specification of neurons of the ventral nuclei, the arcuate and ventromedial nuclei. The proneural gene Mash1 is expressed throughout the basal retrochiasmatic neuroepithelium and loss of Mash1 results in hypoplasia of both the arcuate and ventromedial nuclei. These defects are due to a failure of neurogenesis and apoptosis, a defect that can be rescued by ectopic Ngn2 under the control of the Mash1 promoter. In addition to its role in neurogenesis, analysis of Mash1(-/-), Mash1(+/-), Mash1(KINgn2/KINgn2), and Mash1(KINgn2/+) mice demonstrates that Mash1 is specifically required for Gsh1 expression and subsequent GHRH expression, positively regulates SF1 expression, and suppresses both tyrosine hydroxylase (TH) and neuropeptide Y (NPY) expression. Although Mash1 is not required for propiomelanocortin (POMC) expression, it is required for normal development of POMC(+) neurons. These data demonstrate that Mash1 is both required for the generation of ventral neuroendocrine neurons as well as playing a central role in subtype specification of these neurons.

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PubMed2005

Oxygen modifies artery differentiation and network morphogenesis in the retinal vasculature.

The mechanisms that control differentiation of immature blood vessels into either arteries or veins are not well understood. Because oxygen tension in arteries is higher than in veins, oxygen has the potential to be an instructive signal for artery/vein (AV) differentiation. We test this hypothesis by exposing newborn mice to moderate hypoxia (10% atmospheric oxygen) and studying AV differentiation in the developing retinal vasculature. Forming retinal arteries fail to express the artery-specific markers Delta-like 4 (Dll4) and EphrinB2 during hypoxia. However, other aspects of AV differentiation are retained such as high levels of alpha smooth muscle actin in arterial mural cells and vein-specific expression of the msr/apj gene. The capillary network between arteries and veins is denser, and capillaries expressing the venous marker msr/apj are found in territories normally occupied by arterial capillaries. Thus, it appears that high oxygen in arterial blood is required for arterial expression of Dll4 and EphrinB2, which could be involved in cell-cell repulsion pathways that dictate the normal segregation of arteries and veins.

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PubMed2004

Periodic Delta-like 4 expression in developing retinal arteries.

During vascular development, Notch signalling plays important roles in cell-cell communication and cell fate decisions. We studied expression of Notch 1-4 and its ligand Delta-like 4 (Dll4) in the developing retinal vasculature. Dll4 mRNA is strongly expressed in endothelial cells at the very tips of growing vessels ('tip cells') and also in arteries, where it is expressed in a segmented 'tiger's tail' pattern. This implies that developing retinal arteries contain different types of endothelial cells, Dll4-positive and Dll4-negative. The Dll4-positive stripes do not correspond to any obvious morphological property of the vascular network but correlate to some extent with the distribution of platelet derived growth factor B (PDGF-B) mRNA. However, PDGF-B expression is neither as artery-specific nor as clearly segmented as Dll4. Possible target cells for Dll4 signalling are retinal astrocytes (Notch1 positive), arterial pericytes (Notch3 positive) or arterial endothelial cells themselves (Notch4 positive). However, there is no clear reciprocity of Notch and Dll4 expression that allows identification of the interacting cells. Nevertheless, Dll4 stripes are a novel property of immature arteries, the origin and function of which remain to be explained.

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PubMed2003

Role of arteries in oxygen induced vaso-obliteration.

In mice the retinal vasculature develops in the first postnatal week by spreading from the optic nerve head towards the retinal periphery. During this growth period, exposure to hyperoxia causes vaso-obliteration of capillaries in the retinal center but not in peripheral regions. High oxygen levels lead to downregulation of vascular endothelial growth factor (VEGF), an important survival factor for vascular endothelial cells, which could explain the vaso-obliteration caused by hyperoxia. However, it is not clear why only capillaries in the center of the retina are affected. We therefore investigated how capillary obliteration correlates with VEGF mRNA distribution by in situ hybridization in retinal whole mount preparations. In mouse pups reared under normoxic conditions VEGF mRNA was detectable across the entire vascular network but was virtually absent in the immediate vicinity of arteries. This was true along developing retinal arteries but also around the optic nerve head through which the entire arterial blood supply for the retinal and hyaloid vasculature passes. In these areas capillaries were absent, resulting in so-called capillary free zones. Exposure to hyperoxia caused an expansion of areas with low VEGF mRNA which correlated with capillary obliteration in these regions. Combined capillary obliteration around the optic nerve head and along retinal arteries lead to a large capillary free zone in the center of the retina. Thus, our observations suggest that hyperoxia affects the retinal vasculature by reducing VEGF mRNA levels near arteries and causing a widening of capillary free zones.

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