Date of Award

1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Diane C. Darland

Abstract

One of the characteristics unique to mammalian evolution is the development of the neocortex. The neocortex is a highly ordered six-layered structure, the development of which is tightly regulated. The formation of the cortex is concomitantly dependent upon an outward expansion of the neuroepithelium, a tissue from which all of the neuronal subtypes and glia are born and differentiated, and the investment of blood vessels from the outer pial surface. Orchestration of neurogenesis and blood vessel investment, or angiogenesis, in the cortex is critical for development; however, these processes are often studied independent of one another. While independent investigation of neurogenesis can simplify a study, by removing the potentially confounding variable of angiogenesis, this reductionist approach ignores the fact that the two processes, neurogenesis and angiogenesis, are dependent upon each other and intimately linked.

Many growth factors and transcription factors have roles in both angiogenesis and neurogenesis. Members of both the Notch and Inhibitor of DNA binding (Id) family of proteins have been shown to guide differentiation in neural stem cells, as well as to direct the migration of newly sprouting vessels. Another growth factor that has been linked to both angiogenesis and neurogenesis is Vascular endothelial growth factor A (Vegf). Vegf is a pleiotrophic factor linked to a broad range of effects in neurovascular systems including proliferation, migration and differentiation. Vegf and its receptors (VegfR1, VegfR2, Nrp1, and Nrp2) are expressed in many of the cell types critical for neurogenesis and angiogenesis.

The Vegf gene is expressed as three main isoforms in the mouse brain, and these isoforms have distinct biochemical properties based on the presence or absence of a heparin sulfate proteoglycan (HSPG) binding domain. Vegf isoforms with the full HSPG-binding domain are not diffusible in the microenvironment (Vegf188) without proteolytic cleavage, those with a partial HSPG-binding domain are partially diffusible (Vegf164), and those lacking the domain entirely are freely diffusible (Vegf120). The different biochemical properties of the Vegf isoforms allow gradients of Vegf to form in the microenvironment. We hypothesize that it is through these differing gradients of Vegf isoforms, that Vegf can orchestrate neurogenesis and angiogenesis in the cortex. To investigate this, we took advantage of a transgenic mouse model in which mice express single Vegf isoforms (Vegf120 or Vegf188), or combinations of Vegf isoforms (Vegf120/188), and lack the Vegf164 isoform. These mice represent a loss of function model (no Vegf164) as well as misexpression models through which we can test the role of Vegf in cortical neurogenesis and angiogenesis.

Additional Files
Cain_TabIV_Appendix.pdf (2580 kB)
Appendix - Table IV
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