OBJECTIVES:

To understand the interplay between intrinsic transcription factors and extrinsic signals in retinal cell fate determination;
To appreciate the role of mechanical forces in shaping apical extracellular matrix structures such as the Drosophila corneal lens;
To understand how the Drosophila corneal lens can be used to model human corneal disease.

LECTURE SUMMARY: The Drosophila corneal lens is a precisely curved structure made entirely of apical extracellular matrix that resembles the mammalian cornea in its ability to focus light onto the photoreceptors. The non-neuronal cone and pigment cells that secrete the corneal lens differentiate from the same progenitor cells in the eye imaginal disc as the photoreceptors. Photoreceptor differentiation requires a zinc finger transcription factor, Glass. scRNA-Seq data shows that most photoreceptors arrest early in their development in glass mutants, but R8, the first photoreceptor to form in each cluster, is less affected. Similarly, Epidermal Growth Factor Receptor (EGFR) signaling is required for the differentiation of all photoreceptors other than R8. We find that in a heterologous context, Glass and EGFR signaling interact synergistically to induce neuronal gene expression. In addition to its role in photoreceptors, Glass also acts autonomously in the non-neuronal cells of the eye, activating distinct sets of target genes in each cell type. As these cells differentiate, they secrete corneal lens material and sculpt it into the correct shape. We find that the transcription factor Blimp-1 is essential for the corneal lens to develop its external curvature, and that it acts specifically in the secondary and tertiary pigment cells that lie beneath the periphery of the corneal lens. The target genes regulated by Blimp-1 include several that encode Zona Pellucida (ZP) domain proteins, which are known to attach apical extracellular matrix to the plasma membrane. One of these proteins, Dusky-like (Dyl), appears to control corneal lens shape through attachments to the underlying cells. Cone and primary pigment cells that lack dyl undergo apical constriction and apical-basal contraction, resulting in inward curvature of the corneal lens. Artificially inducing a similar apical constriction is sufficient to reproduce the change in corneal lens shape. However, Dyl is only transiently expressed in the retina; our data suggest that it reorganizes other ZP domain proteins to establish a more permanent connection between the corneal lens and the underlying cells. The Blimp-1 mutant phenotype is not identical to the dyl phenotype, and may be due in part to up-regulation of genes that Blimp-1 normally represses. We found that reducing the expression of one such gene, CG43333, restores a more normal corneal lens shape to Blimp-1 mutants. Interestingly, CG43333 is a homologue of TGF beta-induced protein, a major human corneal protein that is mutated and accumulates in numerous corneal dystrophies. Blimp-1 is expressed in human corneal epithelial cells and enriched in the limbus, where stem cells reside. Our results suggest that Blimp-1 may regulate conserved targets in fly and human corneal tissues, making the Drosophila corneal lens a useful model to study human corneal development and disease.

See https://med.nyu.edu/faculty/jessica-e-treisman.
For more information go to https://oir.nih.gov/wals