Genetic Basis of Patterning and Growth in Drosophila Eye

Singh, Amit

Abstract

In multi-cellular organisms, axial patterning is required for transition of a mono-layered epithelium of an organ primordium to a three-dimensional organ by delineation of antero-posterior (AP), dorso-ventral (DV), and proximo-distal (PD) axis. We employ Drosophila melanogaster (fruit fly) eye model to study the highly conserved fundamental process of (axial) DV patterning and growth. During eye development, DV patterning precedes AP and PD axis patterning, and forms dorsal and ventral compartments. The border between the dorsal and the ventral domains of eye, termed equator, is the site for upregulation of the Notch (N) signaling, which regulates cell proliferation and differentiation. Discerning the mechanism of axes determination (DV) is crucial for our understanding of organogenesis as the problems with DV delineation results in developmental/ birth defects in flies to humans. Our long term goal is to understand the genetic basis of DV patterning which is established by interactions of the dorsal selector genes and the ventral genes. The Drosophila eye begins from a ventral equivalent state on which the dorsal fate is established by onset of expression of GATA-family transcription factor Pannier (Pnr), the secreted morphogen Wingless (Wg), and Iroquois (Iro-C) family proteins. In the dorsal eye, pnr is not the sole regulator of Wg expression. It strongly suggests that there may be other dorsal eye genes that are yet to be identified. To understand the molecular genetic basis of DV patterning, we will analyze the (1) Determine the role of new dorsal eye gene dve during eye development, (2) Investigate genetic hierarchy of dorsal eye patterning genes, and (3) Whether DV patterning and Hippo signaling may co-regulate Wg during DV patterning.. Given that the genetic machinery is conserved, we will also test the role of SATB1, a human ortholog of dve in the eye, which is known to be involved in growth regulation, cancer and metastasis. These studies will help discern (a) a new role of dve in axial patterning and complex process of retinal differentiation, (b) role of dve in delineating eye versus head boundary and (c) genes involved in growth and cancer do have function in patterning and differentiation, (d) How do independent pathways interact to regulate growth and patterning in the developing eye?. These studies will have significant bearings on understanding the (i) molecular basis of developmental defects caused by mutations in the human homolog of Drosophila dve, and (ii) genetic mechanism of early developmental events during organogenesis in higher vertebrates too. In humans and other vertebrates, DV polarity of the retina regulate the retinal axon projections to the brain. These studies will shed light on the role of early developmental events on the retinal axon projection to the brain during normal development and disease. The knowledge generated from these studies is expected to elucidate fundamental mechanisms in patterning and growth of normal visual function and within the context of retinal disease and birth defects in the eye.

Public Health Relevance

This proposal utilizes fruit fly Drosophila eye model to discern the genetic mechanism of axial patterning and growth, critical and fundamental processes required for the transition of a single layer of cells into a three-dimensional organ. Given the conservation of genes required for these most fundamental developmental biological processes, we propose to study the (i) molecular genetic function of DV patterning genes in patterning and growth (ii) and their interactions with the evolutionarily conserved growth regulatory Hippo signaling pathway with emphasis on discerning crosstalk between two core pathways that are known to act independently in regulating Wingless signaling and thereby determining positional fate and regulate growth during organogenesis. These studies will have significant bearing on understanding the genetic basis of organogenesis, cause of abnormal processes that lead to visual system birth defects, retinal defects, and therefore is of immediate relevance and importance to human health.