Speaker
Description
"During neocortex development neural stem progenitor cells display polarity features that are fundamental in determining their identity and fate. Interestingly, Golgi apparatus (GA) is differentially positioned in the two main neural stem cell types, apical and basal progenitors (APs and BPs, respectively). GA is known to be the main hub for glycosylation and defects in GA and glycosylation can affect brain development. Previous results from our lab suggested that the GA fragmentation in mouse embryonic brain and in human brain organoids favors the APs to BPs cell fate transition. To investigate the influence of GA on cell identity and lineage progression during brain development, we leverage the genetics of Congenital Disorders of Glycosylation (CDGs), a group of multi organ rare and ultra-rare diseases caused by mutations of structural proteins or enzymes in the secretory pathway. We focus our attention on COG5-CDG, caused by mutations in COG5, a GA-resident proteins involved in Golgi homeostasis and function. COG5-CDG patients suffer from neurodevelopmental defects, including seizures and microcephaly. The knock-down of COG5 in human brain organoids through electroporation causes the fragmentation of Golgi apparatus, an increase in Tbr2-positive intermediate progenitors (IP) and an increase in the Ctip2-positive neuronal population. No significant changes were found at the level of apical progenitors. These results suggest an effect of Golgi apparatus on NPCs identity and fate transition.
To gain further insight in the contribution of COG5, and more in general of GA, on brain development, we generated human brain organoids from iPSCs obtained from two siblings harboring a mutation in COG5. We are now combining different phenotyping strategies including staining for fate markers, scRNA seq to follow lineage progression and glycomics to investigate the effect of COG5 mutation on the glycosylated proteins and lipids and correlate the glyco-makeup of progenitors with their fate choice.
In conclusion, by leveraging the genetics of a human glycosylation disease we aim at filling the gap between the cell biological role of GA in progenitor cells and the pathophysiological manifestations associated with defective GA glycosylation."
| Author(s) | Martina Polenghi1, Elena Restelli1, Giovanni Faga1, Francois Foulquier2 and Elena Taverna1 |
|---|---|
| Affiliation(s) | "1 Human Technopole, Milan, Italy 2 University of Lille, Lille, France" |
