Current Biology, Vol. 14, R62–R64, January 20, 2004, ©2004 Elsevier Science Ltd. All rights reserved. DOI 10.1016/j.cub.2003.12.045
Neuronal Development: Specifying a
Hard-Wired Circuit
Lisa Stowers
The formation of neuronal circuits that relay distinct
olfactory information is thought to depend on cues
provided by pre-synaptic receptor neurons. But direct
visualization of second order neurons in Drosophila
now suggests that dendritic targeting occurs independently of interactions with incoming sensory
neurons.
During sensory development, abundant neurons are
created in the brain that become functional by precisely
extending processes to synapse with determined
targets. In contrast to the visual or somatosensory
system, olfactory information is mediated by a large
number of distinct receptor neurons, randomly intermingled in the olfactory epithelium, and the axons from
cells expressing identical ligand receptors precisely
converge on a defined second order neuron (Figure 1).
This poses a number of molecular challenges to ensure
that a stereotyped, hard-wired circuit properly develops
so as to mediate perception. Work on development of
the olfactory system in Drosophila is beginning to elucidate the principles that underlie this process.
Neuronal circuit formation has been well characterized in the visual system, where positional sensory
information from neighboring neurons must be preserved at each synapse so as faithfully to represent
the environment [1,2]. Gradients of ephrins and their
receptors govern the position of synapse formation of
individual neurons, which is then refined by coordinated neuronal activity [3]. This, however, does not
appear to be the only strategy for specifying neuronal
targets, as demonstrated in the mammalian olfactory
system where activity is dispensable [4,5] and the
only identified essential molecular components of this
process are the olfactory receptor genes themselves
[6,7]. One might assume that the olfactory receptors
detect ligand cues which are important for correct
wiring of the system, but at present no cues of this
kind have been discovered.
Convergence of the sensory neurons is only half of
this complex process. The dendrites of the second
order neurons — mitral cells in vertebrates or projection
neurons in invertebrates — are also targeted to this
defined region to form glomeruli (Figure 1) [8]. Several
studies on vertebrates and invertebrates have suggested that the wiring pattern at this level of the olfactory system is instructed by the incoming receptor
neurons. Specifically, genetic ablation of the mitral cells
in the mouse was found not to disrupt the convergence
and stereotyped position of incoming receptor neurons
The Scripps Research Institute, 10550 North Torrey Pines
Road, ICND 222, La Jolla, California 92037, USA.
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[9]. In the moth, removal of the antennae, and thus the
receptor neurons, prevented normal glomerular formation [10], while surgical dissection of projection neurons
did not disrupt receptor neuron convergence [11]. And
in Drosophila mutants where there is a failure to establish a proposed pioneer class of receptor neurons, the
development of glomeruli is disrupted [12]. Together,
these studies suggest that specific wiring at the first
relay in the olfactory system is precisely patterned by
receptor neurons which instruct the second order
neurons to organize appropriately.
Liqun Luo and colleagues [13] recently reasoned that,
to elucidate the mechanisms of stereotypic wiring, it is
essential to identify the order of spatial patterning of the
incoming receptor neurons and the outgoing projection
neurons in the antennal lobe. To do this, they used a
sophisticated genetic strategy [14] in which single cell
clones or neuroblasts were labeled with a marker that
allowed visualization of specific neurons. This strategy
has now revealed [13] that projection neurons occupy
their ultimate restricted and specific regions of the
developing antennal lobe hours before the arrival of the
axons of olfactory receptor neurons. This indicates that,
in Drosophila at least, the dendrites of the projection
neurons are capable of specific stereotyped targeting
in the absence of any physical contact with olfactory
receptor neurons.
Jefferis et al. [13] further investigated the origins of
the cues that direct the dendritic patterning of the
projection neurons. They hypothesized that the antennal lobe of Drosophila is so small (about 30 µm in diameter) that the approximately 50 different patterning
domains within it — the glomeruli — are most likely
established by cues within the developing lobe that are
cell-surface bound, rather than freely diffusible or acting
at long distances. Further genetic experiments allowed
the authors to eliminate as sources of these putative
cues the larval lobe, adult glial cells and a subset of
local interneurons. They found that the position of each
of these candidate cue sources remains distinct from
projection neurons during the time of pattern formation.
Dendrites of projection neurons are the primary
component of the developing antennal lobe, and different classes of projection neurons may have differential molecular profiles that depend on their cell
lineage and birth order [8,15]. On the basis of their
observations of cell location and the timing of projection neuron development, Jefferis et al. [13] suggest
that patterning of projection neuron dendrites may
have a significant self-organizing component, involving
dendro–dendritic interactions. They propose that the
mechanism may include homotypic attraction and/or
heterotypic repulsion from surrounding dendrites to
sort, pattern and specify the developing antennal lobe.
It is not immediately clear how this conclusion can be
reconciled with the earlier observations suggesting that
the axons of incoming olfactory receptors have an
instructive role in development of the circuit [16–19].
Current Biology
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Figure 1. Convergence of olfactory
receptor neurons and projection neurons
in the antennal lobe of Drosophila.
Neurons expressing individual olfactory
receptors are intermingled at the periphery of the animal to detect odorants.
Axons of similar neurons, depicted by the
same color, converge upon dendrites of
projection neurons to form glomeruli in
the antennal lobe. Recent findings [13]
indicate that dendrites of specific projection neurons robustly target to appropriate glomeruli prior to arrival of receptor
neuron axons. Corresponding mammalian
structures are indicated in parentheses.
Projection neurons
(mitral/tufted cells)
Mushroom body
lateral horn
(olfactory cortex)
Olfactory receptor
neurons
Glomeruli
Antennal lobe
(Olfactory bulb)
These earlier studies, however, mostly relied on the formation of mature, discrete glomeruli to indicate the
occurrence of patterning. Recently developed genetic
techniques offer a superior resolution, making it possible to investigate the development of wiring specificity
with a higher accuracy than previously possible. Jefferis
et al. [13] propose that spatial patterning and glomerular formation may be two distinct processes. In the
model proposed by Jefferis et al. [13], receptor neurons
and projection neurons both have self-governing patterning mechanisms, each capable of forming a ‘protomap’ that interacts to form the mature, coherent
glomerular structure.
It will be of great interest to determine how the receptor neurons and projection neurons are directed to their
destined targets (Figure 2). Do the pre-synaptic and
post-synaptic cells use common intrinsic or extrinsic
mechanisms to coordinate their specific patterning? Is
activity dispensable for the refinement of connectivity?
Interestingly, Jefferis et al. [13] observed that the projection neurons first extend axons to their targets prior
to dendrite outgrowth. With this in mind, does the molecular landscape of the projection neuron axons direct
Receptor neuron
Projection neuron
?
Current Biology
Figure 2. Wiring of the Drosophila olfactory system.
The axons of receptor neurons and the dendrites of the
projection neurons are both targeted autonomously to specific
locations in the antennal lobe. The cues that guide each neuron
type are still unknown, but dendro–dendritic interactions may be
one mechanism that contributes to the wiring specificity [13].
Current Biology
dendritic patterning? Are the mechanisms that generate specific wiring conserved between the mouse and
Drosophila? Recent technical advances should enable
these issues to be clarified. The power of genetic analysis in Drosophila and mouse is providing a surprising
picture of the development mechanisms which ensure
that those neurons that generate olfaction perception
are precisely wired.
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