ayout 1 - EMBL Grenoble

EMBL Research at a Glance 2009
Francesca Peri
PhD 2002, University of
Cologne.
Postdoctoral research at the
Max Planck Institute for
Developmental Biology,
Tübingen.
Group leader at EMBL since
2008.
Microglia: the guardians of the developing brain
Previous and current research
During brain development neurons are generated in great excess and only those that make functional
connections survive, while the majority is eliminated via apoptosis. Such huge numbers of
dying cells pose a problem to the embryo, as leaking cell contents damage the surrounding environment.
Therefore, the clearance of dying cells must be fast and efficient and is performed by a
resident lineage of ‘professional’ phagocytes, the microglia. These cells patrol the entire vertebrate
brain and sense the presence of apoptotic and damaged neurons. The coupling between the death
of neurons and their phagocytosis by microglia is striking; every time we observe dead neurons
we find them already inside the microglia. This remarkable correlation suggests a fast-acting communication
between the two cell types, such that microglia are forewarned of the coming problem.
It is even possible that microglia promote the controlled death of neurons during brain
development. Despite the importance of microglia in several neuronal pathologies, the mechanism
underlying their degradation of neurons remains elusive.
The zebrafish Danio rerio is an ideal model system to study complex cell-cell interactions in vivo.
As the embryo is optically transparent, the role of molecular regulators identified in large-scale forward
and reverse genetic screens can be studied in vivo. Moreover, a key advantage of the system
is that zebrafish microglia are extremely large, dynamic cells that form a non-overlapping network
within the small transparent fish brain. Labelling microglia, neurons and organelles of the microglial phagocytotic pathway simultaneously
in the living zebrafish embryos allows us to image for the first time the entire microglial population to study the interaction between
neurons and microglia.
Future projects and goals
We plan to exploit the system at the cell biological level to understand how the microglia cells find, engulf and digest dying and sick neurons.
We are generating methods for real time identification of apoptotic neurons and controlled-killing of neurons under the microscope to monitor
the response of the surrounding microglia in vivo. We predict that dynamic changes in cell branching behaviour will reveal functionally
significant interactions between microglia and the neighbouring cells. Moreover, we are currently using a number of forward and reverse genetic
approaches to identify the molecules that control the interactions between
these two cell types. A recent genetic screen has led to the isolation of several mutant
lines where the response of microglia to neuronal apoptosis is affected, and
we are cloning the underlying genes.
The aim of our work is to advance our understanding of microglial-mediated neuronal
degeneration, a hallmark of many neuronal diseases as common as
Alzheimer’s and Parkinson’s disease.
Microglia (green) and neurons (red)
in the zebrafish embryonic brain.
Selected references
Peri, F. & Nusslein-Volhard, C. (2008). Live imaging of neuronal
degradation by microglia reveals a role for v0-ATPase a1 in
phagosomal fusion in vivo. Cell, 133, 916-927
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