Abstract
Purpose :
During eye development, the optic primordia undergo a complex series of morphogenetic events that culminate in the formation and placement of each tissue in the eye. One critical step in optic cup morphogenesis is the formation and closure of the choroid fissure. The choroid fissure is a transient structure located in the ventral optic cup that enables vasculature cells to enter the eye, and ganglion cell axons to exit the eye. While some factors have been identified that influence closure of the fissure, the molecular and cellular mechanisms that mediate fusion remain poorly understood. This is a critical gap in our knowledge because when choroid fissure closure fails, a form of pediatric blindness, termed coloboma, results. Recently, MITF was shown to be mutated in a subset of human coloboma patients, but how MITF functions to facilitate choroid fissure closure is still unknown. Mitf genes have a variety of roles including cell survival, pigmentation, motility, and cell cycle regulation. Moreover, they are expressed in several compartments of the eye, including the retinal pigmented epithelium and the neural crest derived-periocular mesenchyme, suggesting several possible mechanisms.
Methods :
We utilized a mitf mutant zebrafish line to understand how mitf contributes to choroid fissure closure. In order to determine with which cell type mitf acts, cell transplantation and rescue experiments were performed. in vivo imaging and molecular assays were utilized to determine the mechanism through which mitf function enables normal choroid fissure closure.
Results :
Analysis of cell transplant experiments revealed that wildtype neural crest cells rescued the coloboma phenotype, while wildtype retinal cells do not. In addition, mitf mutant neural crest cells exhibited increased cell death and a decreased ability to migrate to the eye.
Conclusions :
These data support a model in which mitf transcription factors act within the cranial neural crest cells to promote cell survival and migration. In turn, neural crest cells play a pivotal role in closure of the choroid fissure. The findings will ultimately aid in our understanding of early eye development and provide a foundation for the prevention and treatment of pediatric ocular diseases such as colobomas.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.