Arun Rushton
Pronouns: He/Him
Research Mentor(s): Yuji Mishina
Research Mentor School/College/Department: Biological and Material Sciences / Dentistry
Program: UROP
Session: Session 5 (2:40pm – 3:30pm)
Authors: Arun Rushton, Hiroki Ueharu, Yuji Mishina
Abstract
Alveoli play an essential role in the process of breathing; they are the site at which the exchange of carbon dioxide and oxygen takes place in the lungs (Herzog et al.). As a result, the function of the lung is highly related to the development of its alveoli. A key part of the development of the alveoli is the differentiation of common progenitor cells into alveolar type one (AT1) and type two (AT2) cells, typical development leads to an alveolus made up of about 85% AT1 cells and the other, AT2, cells being distributed throughout. While AT2 cells make up about 15% of the cells in an alveolus, they only make up about 5% of the surface area (Herzog et al.). In addition to the direct differentiation from the common progenitors that happens during embryogenesis, AT1 cells differentiate from AT2 cells postnatally, through a mechanism regarded as transdifferentiation, especially upon injury. We and others reported that disruption of Podoplanin (Pdpn), a marker gene for AT1 cells, abolishes the development of AT1 cells thus leading to perinatal lethality. We recently found two distinct groups among the homozygous Pdpn knockout mice, one group which died shortly after birth and one that survived. Between those two groups, the clumping of AT2 cells was significantly more common among the group that died. Additionally, morphological analysis showed that the internal areas of their alveoli were also significantly smaller, indicating a reduced ability to breathe. The surviving group of Pdpn homozygous knockout mice showed far fewer clumps of AT2 cells. Based on these observations, I hypothesized that in the survived mutant mice AT2 cells differentiate into AT1 cells during embryogenesis to compensate lack of AT1 cell development from the common progenitors. To understand the molecular reasons for this change, bulk RNA sequencing was conducted. Subsequent qPCR testing indicated elevated expression of LRG1 in the surviving group of the homozygous knockout mice, compared to both a heterozygous control group and the homozygous group that died. Immunohistochemical analysis of embryonic lungs also showed higher LRG1 protein levels in the surviving homozygous knockout group. My current working hypothesis is that the elevated LRG1 promotes the transdifferentiation of AT2 cells into AT1 cells resulting in a significant improvement in survival rate for the Pdpn homozygous knockout mice.
