The roles of podoplanin and clec-2 in the development and maintenance of the cerebral vasculature

Lowe, Kate (2015). The roles of podoplanin and clec-2 in the development and maintenance of the cerebral vasculature. University of Birmingham. Ph.D.

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Abstract

The C-type lectin-like receptor, CLEC-2, is constitutively expressed on platelets, with reported expression on a number of leukocyte subsets in adult mice. Constitutive or platelet-specific deletion of CLEC-2 in mice induces cerebral haemorrhaging by midgestation. In this thesis, I investigated the basis of this defect, hypothesising that it is mediated by the loss of CLEC-2 activation by its endogenous ligand, podoplanin, expressed on the developing neural tube. Podoplaninfl/fl mice were crossed to mice expressing PGK-Cre to induce deletion of podoplanin at the two-cell stage. Developing blood vessels were visualized by 3-dimensional microscopy and found to be aberrantly patterned in CLEC-2- and podoplanin-deficient mice, culminating in widespread cerebral haemorrhaging by mid-gestation. Haemorrhages were also observed following Nestin-Cre driven deletion of podoplanin on neural progenitors and following deletion of the platelet integrin, αIIbβ3. Together these studies support that neuro-epithelial-derived podoplanin interacts with platelet-CLEC-2 to guide the maturation and integrity of the cerebral vasculature and to prevent haemorrhage by stimulating platelet aggregation. Using tamoxifen-inducible deletion of CLEC-2 in adult mice, the expression profile of CLEC-2 was investigated and shown to be restricted to platelets and circulating B-lymphocytes and CD11bhigh Gr1high myeloid cells. Furthermore, loss of CLEC-2 in adult mice was shown to be dispensable for maintaining blood-brain barrier permeability.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Watson, Steve P. UNSPECIFIED UNSPECIFIED
Licence:
College/Faculty:	Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department:	School of Clinical and Experimental Medicine, Centre for Cardiovascular Sciences
Funders:	Medical Research Council
Subjects:	Q Science > Q Science (General) R Medicine > R Medicine (General)
URI:	http://etheses.bham.ac.uk/id/eprint/5791

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• The roles of podoplanin and clec-2 in the development and maintenance of the cerebral vasculature. (deposited 27 Apr 2015 10:18) [Currently Displayed]

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