|Ph.D Student||Shklover Jeny|
|Subject||The Role of the JNK Pathway during Development of the|
Drosophila Central Nervous System
|Department||Department of Medicine||Supervisor||Dr. Estee Kurant|
|Full Thesis text|
A large number of neurons die through apoptosis and are efficiently removed by phagocytic glia during the development of the central nervous system (CNS). Efficient removal of apoptotic neurons is crucial for the establishment and maintenance of a functional CNS and must be tightly regulated. Despite its great biological importance, the molecular mechanisms underlying the relationship between neuronal apoptosis and glial phagocytosis remain unclear. We use the developing CNS of Drosophila melanogaster as a model system for studying the molecular basis of glial phagocytosis of apoptotic neurons, an evolutionary highly conserved process.
Our study demonstrates that Drosophila JNK (dJNK) pathway is normally involved in developmental neuronal apoptosis but not in apoptotic cell clearance. However, gain-of-function of dJNK signaling in embryonic neurons induces dJNK pathway activation in glia, which promotes glial phagocytosis of apoptotic cells. Importantly, this upregulation of phagocytosis is not accompanied by elevated expression levels of the phagocytic receptors SIMU and DRPR and the engulfment ability of phagocytic glia, but it promotes degradation of engulfed apoptotic particles inside phagosomes. The proposed mechanism may be important for removal of damaged neurons in the developing and mature CNS.
In a second part of this work, we discovered a novel
role of the Drosophila sole TNF-alpha homolog, eiger, in
eliminating damaged neurons during development. We demonstrate that Eiger,
which is specifically expressed in embryonic neurons and glia, is not involved
in developmental neuronal apoptosis or apoptotic cell clearance. However, we
provide evidence that Eiger is non-autonomously required for damage-induced
In sum, our work revealed novel molecular mechanisms of neuronal apoptosis and glial phagocytosis of apoptotic neurons in Drosophila. These findings open new directions in the understanding glial biology in higher organisms.