From susceptibility to signals: How cues from the retinal microenvironment influence stem and progenitor cell behaviors - Project Summary
Precisely balanced proliferation and differentiation is required for development, growth, and
repair of the eye. Imbalanced proliferation and differentiation is linked to neurodegenerative
disorders as well as retinal cancers. This project is designed to uncover how cells in the growing
zebrafish eye transition from proliferation to differentiation. Zebrafish develop rapidly and are
particularly amenable to high-resolution imaging and genetic manipulations, allowing
developmental events to be studied in real time and correlated with genetic, molecular and
cellular changes.
Three specific aims investigate how extrinsic input from growth factors and the underlying
extracellular matrix influence cell proliferation and differentiation in the zebrafish retina.
Aim 1: To uncover the cellular mechanisms downstream of Gdf6a-retinoic acid antagonism that
maintain stem and progenitor cells in the growing zebrafish retina
This aim tests the hypothesis that retinoic acid (RA) pathway activity favors symmetric,
differentiating divisions in the growing retina. It employs genetic and pharmacological
manipulations of RA signaling and time-resolved confocal imaging to analyze cell division plane
orientation and map the composition of clones arising from single retinal progenitor cells.
Aim 2: To explore how dorsal-ventral retinal patterning impacts eye growth and development
This aim asks how dorsal signaling pathways regulated by Gdf6 guide changes in cell shape,
size, orientation, and proliferative behavior within a stem cell niche in the zebrafish retina by
employing genetic manipulations coupled with quantitative image analyses.
Aim 3: To probe the relationship between a specialized basement membrane and stem-cell
mediated growth in the zebrafish retina
This aim builds on preliminary data linking changes in basement membrane organization with
maintenance of retinal stem cells. It employs established methods and novel transgenic lines to
test the hypothesis that deposition of Collagen 15a1b, establishes a specialized extracellular
matrix that (1) anchors stem cells at the retinal periphery and (2) regulates their proliferation.
Significance: The results from this project will impact our understanding of growth, repair, and
regeneration in the retina and entire central nervous system. Specifically, the data will deepen
our understanding of how extrinsic factors coordinate proliferation, differentiation, and cell
survival. These data will also shed new light on retinal stem and progenitor cell behaviors that
may be leveraged for treating neurodegenerative diseases and neuronal cancers.
