Impact of the Loss of N-Cadherin or Microtubules on Lens Development and Immune Surveillance
The lens is tissue whose structure defines its function, meaning that both morphogenesis and the maintenance of cellular architecture are critical for proper vision. Our studies focus on understanding the process underlying lens development and morphogenesis, with a particular concentration on the process of lens fiber cell elongation and migration, as well as how this tissue responds to injury and loss of its normal morphology. Tissue development is known to depend on both cytoskeletal proteins as well as cell-cell junctions, to allow for force, directionality and collectivity of neighboring cells. Our studies focus particularly on N-cadherin, the most prominently expressed cadherin in the lens, as well as microtubules, an understudied cytoskeletal element in the lens system. Using a lens specific conditional knockout mouse model, we are able to investigate the role of N-cadherin in lens morphogenesis and find that its functions are interestingly not required to maintain cell-cell adhesion, but rather impact the migration of lens fiber cells through regulation of both myosin and Rac1. This same process of fiber cell elongation is also investigated in the whole lens organ culture system using the microtubule depolymerizaing agent, nocodazole. These studies indicate that the stable microtubule population is necessary for fiber cell morphogenesis through regulation of myosin and actin. Most interestingly, we discover an association between these stable microtubules and N-cadherin cell-cell junctions, and thus we conclude that this elongation and truly migratory process relies on the interplay between the cytoskeleton, cell-cell junctions and myosin motor proteins. We also demonstrate that dysmorphogenesis, either drug-induced or the result of protein knockout, are perceived by the lens as tissue injury, with a resultant immune response to sites of injury, proving that the lens is not in fact an immune privileged tissue. This population of immune cells, whether arising from endogenous sources or potentially from other sites in the eye, are capable of producing extracellular matrix as part of this potential wound healing response. These results provide insight into the lens as a model system both for development and degeneration.
Logan, Caitlin M, "Impact of the Loss of N-Cadherin or Microtubules on Lens Development and Immune Surveillance" (2019). ETD Collection for Thomas Jefferson University. AAI13811288.