טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentFlint Brodsly Naama
SubjectElucidating a Genetic Network that Maintains the
Differentiated-State of Adult Drosophila
Melanogaster Gut Enterocytes
DepartmentDepartment of Medicine
Supervisor Professor Amir )Oryan )Orian


Abstract

A hallmark of aging is the inability of aging cells and tissues to maintain their differentiated identity. This inability results in the emergence of age-related diseases such as neurodegeneration, metabolic disorders and cancer.

Yet, not much is known about the molecular networks that maintain the identity of fully differentiated cells in adult regenerating tissues and the consequences of de-regulation of this network during aging.

The Drosophila melanogaster is a powerful model organism for studying cellular, tissue and organismal aging. Drosophila is characterized by a relatively short life-span, and four-week-old flies are already considered as aging animals. Importantly, the molecular mechanisms and genes that regulate cell identity, longevity and aging in the fly are highly conserved with that of humans. Drosophila also offers broad genetic and genomic tools, and well-characterized genomes. However, the molecular network that maintains Enterocytes (ECs) identity and its perturbation in aging is relatively unknown.

In this dissertation, I first characterized the cellular and molecular changes that are characteristic of the aging intestinal epithelia. I found that during aging, the Drosophila midgut loses its epithelial integrity and the fully differentiated ECs are unable to maintain their identity.

Second, in searching for identity regulators I found that the transcription factor Hey supervises the identity of differentiated ECs in the adult Drosophila midgut. Lineage tracing of ECs established that Hey-deficient ECs lose differentiated identity and are unable to maintain their unique nuclear organization. Orchestrating this organization is Hey. Hey maintains enhancers’ activity and nuclear lamins expression, and remodels nuclear architecture from a stem cell configuration into a differentiated one. Moreover, during aging levels of Hey decrease and ECs are unable to maintain their identity.