Novel homeostatic functions of Galectin-3 in embryonic and adult neurogenesis
Dr. Francis Szele an associate professor of Developmental Biology from University of Oxford gave a talk at the Center for Developmental Neurobiology as part of the 2021-2022 “NEUReka!” seminar series.
Dr. Szele began the talk by giving a brief introduction about the structure of SVZ Subventricular zone, which contains semi-activated inflammatory cells that migrate toward injuries. Dr. Szele used two-photon microscopy to monitor the behaviour of neuroblasts over the course of 3 hours the cells kept migrating up to 18hours. This showed how dynamic the process of neurogenesis and migration of cells.
He then used electroporation to test the function of SVZ, which is a simple and easy technique that tests mechanisms in the tissue, to make transgenic mice by knockout or knockdown the gene of interest. The application of this technique is done by injecting electrical current into lateral ventricles that have been injected with knockdown plasmids. Szele’s research focuses on Galectin-3 a proinflammatory protein, which is important for apicobasal polarity, Alzheimer disease and neuroblast migration. Gal-3 is expressed highly in ependymal cells and SVZ cells. Cortical injury was used as a model to study the expression of immune cells, and by using CD45 marker, Szele found that 99% of CD45 cells are microglia and are highly expressed in the SVZ, but few days later there was no difference between injured and non-injured animals. This is likely because microglia activation is specifically regulated in SVZ. Interestingly, by using different disease models, Szele explored two main points about SVZ: the inflammatory response of SVZ is unpredictable and different in adjacent tissues. Szele’s group is now collaborating on artificial intelligence to study the different activation states of microglia cells.
Galectin, is a protein family that contains 15 members, and act as inflammation regulators in mammals. One member of the Galectin family, Gal-3, is unique because it has one carbohydrate recognizing domain. Moreover, Gal-3 has multiple mechanisms of action, but the most important mechanism is to act as toll-like receptor-4 to activate microglia. The speaker again confirmed that Gal-3 is expressed selectively in SVZ and ependymal cells in healthy animals. They also found ependymal cell ciliary loss in Gal-3 knockouts. The knockout of Gal-3 caused a significant reduction in the number of astrocytes and oligodendrocytes postnatally. Similarly, the overexpression of Gal-3, produce more astrocytes, which mean oligodendrocytes switch to astrocytes, so Gal-3 is also likely involved in fate choices.
In addition, Szele’s group studied the effect of Gal-3 on BMP signaling, where they found the knockout of Gal-3 reduced BMP signaling and vice versa. Particularly, knocking out the BMP receptor (BMPR1), indicated that the Gal-3 is necessary for glial genesis. Intriguingly, Gal-3 also act as a negative regulator of Wnt signaling and has a role in apicobasal polarity. Gal-3 is expressed embryonically in mouse brain, and in the human pallium at 17 PCW. It is also expressed in neural rosettes in ESC. For general knowledge, neural rosette is not equal to apicobasal polarity, but it is used as proxy.
The speaker then moved to the subject of inhibition Gal-3 pharmacologically using MCP, where they noticed the rosette come back after certain time due to the genetic plasticity. Last but not least, Szele’s group tried to find which is the molecule of rosette, interacting with Gal-3, and they found YAP signaling. Szele’s talk briefly covered the function of Gal-3 in treating Alzheimer disease, by inhibition of Gal-3, which could reduce the amyloid beta aggregates and the knockout of Gal-3 could improve memory.
In summary, he confirmed that SVZ contains semi-activated microglia and Gal-3 has a function on neuroblast migration and postnatal glio-genesis in different ways. Gal-3 has also an effect on neural apicobasal polarity and Alzheimer’s aggravated by Gal-3.