Biology Department
Northeastern University
Boston, Massachusetts

BASIC RESEARCH PROJECT
Analysis of Notch Signaling-mediated Cell Fate determination during Regeneration of the Neural Retina

Scientific Summary: Degeneration of the human retina is irreversible, but Mexican axolotl salamanders have an amazing ability to regenerate their retinas even after their complete removal. We  aim to understand the cellular and molecular mechanisms that enable salamander retinal regeneration, with the goal of eventually applying this knowledge to restoring damaged retinas in humans.

Plans in 2021
The 2020 funding period findings have shaped the future directions of Dr. Monaghan’s research on salamander retinal regenerations.  His team will investigate the specific mechanisms by which Notch signaling controls how cells of retina regrow after an injury and they will focus on understanding how stem cells drive regeneration of the retina.

Specific Aims: Dr. Monaghan’s research will employ a newly developed technique to determine how Notch signaling controls regeneration-specific gene activity in individual cells of the regenerating axolotl retina, including the one whose presence was discovered for the first time, behave during the early stages of regeneration and which mature retinal cells are born from each type.

Progress in 2020
In 2020, Dr. Monaghan developed a technique that reveals cell types in the axolotl retina and their gene activity, which will equip the research team to understand the molecular mechanisms behind regeneration.  The team collected preliminary data suggesting that the Notch signaling pathway may dictate what types of cells regrow in the new retina.  Dr. Monaghan’s research confirmed that the regenerated retina re-establishes its connection with the brain, which is necessary for its functionality.  The research also showed for the first time that the axolotl retina contains a type of glial cell that may serve as stem cells during salamander retinal regeneration.

Purpose of 2020 Project: To correctly regenerate the retina, retinal progenitor cells must produce multiple retinal cell types, such as different kinds of neurons. In other organs, this process is known to be regulated by Notch signaling pathway. Dr. Monaghan proposed to study how Notch signaling regulates production of new neurons and non-neuronal glial cells in the regenerating axolotl retina.

Specific Aims: To address the molecular mechanisms underlying salamander retinal regeneration, which are largely unknown. First, the researchers will uncover how gene activation profile differs between axolotl retinas that regenerate normally and with blocked Notch signaling. Second, they will show what cells in the regenerating retina express those differently activated genes and how Notch signaling controls what types of neuronal and non-neuronal cells regenerate in the new retina.

Results Previously Published: In eyes of newt and axolotl salamanders, the retinal pigment epithelium layer, which is adjacent to the neural retina, provides progenitor cells that rebuild the retina after an injury (Islam et al., 2014; Svistunov and Mitashov 1983). Notch signaling pathway, which facilitates inter-cellular communication and regulates gene expression, is active in the retinal pigment epithelium of the regenerating salamander eye, and its perturbation accelerates regeneration of retinal neurons (Nakamura and Chiba 2007). Notch signaling is also active in the mouse retinal pigment epithelium and can induce cultured mouse retinal cells to adopt some features of retinal photoreceptor neurons (Ha et al., 2017; Osakada et al., 2007). These results suggest that Notch signaling and its target genes may provide the key to unlocking regenerative potential in human retinas.