Webinar Review: Molecular genetic studies of CNS vascular development and disease

Over the course of the semester, our trainees are reviewing webinars in their given fields and preparing abstracts to help colleagues outside their discipline make an informed choice about watching them. As our program bridges diverse disciplines, these abstracts are beneficial for our own group in helping one another gain key knowledge in each other’s fields. We are happy to share these here for anyone else who may find them helpful.

Molecular genetic studies of CNS vascular development and disease

Dr. Jeremy Nathans

December 17, 2020

Columbia University

Taylor JorgensenAnalysis by Taylor Jorgensen:

In this seminar, Dr. Jeremy Nathans summarizes his lab’s work in CNS vasculature development and pathology. This talk was given virtually to students for Columbia University’s Neuroscience Program.

Dr. Nathans describes the important role of canonical Wnt signaling via the effector protein beta-catenin, which can transduce signals in the cell nucleus regarding cell fate determination. The first portion of his talk focuses on the retinal vasculature, where we learn of Norrie’s disease. This human disease is characterized by a mutation in secreted protein Nor that results in congenital blindness, specifically due to the lack of vasculature growth. In mice, a similar protein Ndp was discovered and subsequently studied as a disease model.

It was discovered that the protein norrin activates beta-catenin signaling and acts through the Wnt pathway. Interestingly, stabilizing beta-catenin in endothelial cells rescues the defects in angiogenesis in these mutations. In a similar vein of study, eliminating beta-catenin signaling in all endothelial cells in a wild type embryo blocks angiogenesis specifically in the CNS.

The second portion of this talk shifts to focus on the blood-brain barrier (BBB). Grp124 is introduced as a protein that is a necessary part of the Wnt signaling complex, as knock out models show defects in CNS angiogenesis and BBB integrity. Deficits in the BBB structures are seen in many neurological disorders, making it an important point of research. Further research in transgenic mice show that Wnt signaling is necessary for normal BBB function, and it occurs throughout life. Activating this signaling can cause brain endothelial cells to shift their permeability from tight to leaky or vice versa. Dr. Nathan’s research into permeability continues today with whole genome analyses of regulatory genes in the blood-brain barrier.

Although this seminar is only about 40 minutes in length, it is a very dense talk with little background information. Familiarity with Wnt signaling would be helpful in contextualizing Dr. Nathans’ research, as he focuses on its action in his specific field. I think that this seminar is not something that would be easily accessible to those who are far outside the field of genetics or neuroscience. Overall I found this seminar to be very informative and it will expand your knowledge of the importance of signaling factors in neurovasculature.