Overview
 

We are interested in understanding how the nervous system is assembled during development

Our nervous systems are made up of billions of neurons. Yet our ability to properly interact with our
environment depends on our neurons organizing into discrete networks, comprising specific neuron types
connected through synapses. Given the tremendous cellular diversity of the nervous system, how do
neurons distinguish appropriate and inappropriate synaptic partners, and organize into functional networks
that underlie behavior? Our goal is to identify general molecular and cellular principles that underlie synaptic
specificity and neural network formation.


 
The System

Our research focuses on the Drosophila visual system, which
comprises well characterized neuron types that form stereotyped
patterns of synaptic connections. A highly advanced genetic toolkit
affords precise molecular and cellular control within this system,
allowing neural connectivity to be studied in vivo, at the level of
identified cell types, synapses and molecules, with single cell
resolution. In addition, more than 100 cell types form connections
within the Drosophila optic lobe, which is on par with the cellular
diversity of the vertebrate retina. Thus, the Drosophila visual
system is complex, well characterized at the cellular and synaptic
level, and is genetically accessible. In our opinion, this system
provides an unprecedented opportunity to understand how
complex neural networks are constructed.



Approach

Synaptic specificity

In his Chemoaffinity Hypothesis, Roger Sperry proposed that neurons carry identification tags in the form of
cell surface molecules, that allow them to identify  appropriate synaptic partners amidst numerous
alternatives. However, Sperry-like molecules that control synaptic specificity have remained elusive. Through
gene expression studies we have identified several cell surface families whose members are differentially
expressed by neurons in the Drosophila optic lobe. These include two families of IgSF proteins
(dprs and DIPs) whose members bind heterophilically and are expressed in a matching manner between
synaptically connected neurons. A major goal of our research is to understand whether and how these
molecules regulate synaptic specificity, and determine the gene regulatory networks that give rise to their
expression in specific cell types.














Construction of layered neural networks

In the Drosophila optic lobe, neural connections are arranged in a layer-specific manner. Each layer,
contains the processes of different types of target neurons, and different types of input neurons confine their
synapses to specific layers.
This organizational strategy is conserved across vertebrates and invertebrates,
and is thought to promote precise synaptic connectivity and efficient information processing. Many regions
of the mammalian nervous system are defined by layered patterns of synaptic connections, including the
cerebral cortex, spinal cord and retina. A major goal of our research in the Drosophila visual system is to
identify general molecular and cellular mechanisms underlying the construction of layered networks of
synaptic connections.

Our research and the work of others
indicates layers are not well defined early
in development, but form in a stepwise
manner from broad domains as the
processes of specific cell types are added
in a precise order, unrelated to the time of
birth. We are interested in determining the
molecular and cellular logic controlling the
sequences of cellular interactions that give
rise to specific layers. Our recent research
suggests that layer-specific circuits are
nucleated through use of transcriptional
modules, that cell-intrinsically instruct
targeting to specific layers, and
cell-extrinsically recruit other neurons
(e.g. through activation of secreted
molecules). Our findings, together with
research in laminated regions of the
mammalian nervous system suggest this
may represent an evolutionarily shared
strategy for building neural circuits.



In our research, we utilize a diverse experimental approach that incorporates molecular genetics,
transcriptomics and genomics analysis, confocal and superresolution microscopy, electron microscopy, and
functional imaging. We are also interested in utilizing electrophysiology and behavior to investigate the
consequences of manipulating neural connectivity. The sophisticated genetic toolkit available for Drosophila
and especially for the visual system, provides tremendous opportunities for creative and innovative approaches
to address biological questions. More often than not, we can think of our dream experiment, and find a way
to build flies to make it happen.