View Program - 63rd Annual Drosophila Research Conference

Basement membranes are the oldest, most conserved forms of extracellular matrix and serve to separate tissue layers, provide mechanical support, direct signals to neighboring cells, and insulate tissues from signals. Further, basement membranes are subject to mechanical damage and require dynamic repair mechanisms. Faulty basement membrane repair mechanisms can aid in the progression of diseases such as asthma and diabetes, and diseases of the basement membrane itself, including Alport's syndrome and Goodpasture's syndrome. Therefore, understanding how basement membranes repair will be vital to treating these conditions. Our work utilizes the Drosophila midgut basement membrane to probe repair dynamics. In Drosophila, all major basement membrane components have been conserved but with less redundancy than mammals. Our lab has developed an assay to reproducibly damage the basement membrane and study the repair process. Previously we reported that many aspects of basement membrane repair are shared during homeostasis. Thus, it is unclear whether basement membrane damage is actively detected, or instead, passively repaired by homeostatic mechanisms.

Our recent data suggests basement membrane damage is actively detected. Following damage, there is an increase in the number of enteroendocrine (EE) cells, the major secretory cell type in the gut, and we find that guts without EE cells cannot repair the basement membrane. Additionally, the EE cells are a significant contributor of collagen IV needed to repair damage. Importantly, EE precursor cells express a mechanosensory stretch-activated ion channel, Piezo, raising the possibility that a change in stiffness of damaged basement membranes signals the initiation of repair. Excitingly, Piezo knockout flies are able to maintain basement membrane homeostasis in the adult fly but cannot repair it after damage. This is our first evidence that there is a unique mechanism to detect basement membrane damage and initiate repair. However, to our surprise, Piezo knockout flies also showed an increase in EE cells following damage, suggesting that EE cells are regulated independently of Piezo. This result suggests that Piezo and EE cells function independently to repair basement membrane, raising the question of how Piezo functions in basement membrane repair.

Basement membrane repair dynamics in the Drosophila midgut

**Basement membrane repair dynamics in the Drosophila midgut**