Olfactory map formation in the Drosophila brain: genetic specificity and neuronal variability

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The development of the Drosophila olfactory system is a striking example of how genetic programs specify a large number of different neuron types and assemble them into functional circuits. To ensure precise odorant perception, each sensory neuron has to not only select a single olfactory receptor (OR) type out of a large genomic repertoire but also segregate its synaptic connections in the brain according to the OR class identity. Specification and patterning of second-order interneurons in the olfactory brain center occur largely independent of sensory input, followed by a precise point-to-point matching of sensory and relay neurons. Here we describe recent progress in the understanding of how cell-intrinsic differentiation programs and context-dependent cellular interactions generate a stereotyped sensory map in the Drosophila brain. Recent findings revealed an astonishing morphological diversity among members of the same interneuron class, suggesting an unexpected variability in local microcircuits involved in insect sensory processing.

Introduction

Olfaction depends on the differential activation of olfactory sensory neurons (ORNs) and proper transmission of their activities to the brain. From insects to mammals, olfactory input is spatially organized into distinct sensory channels, which form a discrete neural map in the brain [1, 2, 3, 4]. Based on the specific OR type they express, ORNs in the sensory epithelium fall into distinct functional classes and all ORNs of the same class converge their axons onto a common synaptic target in the brain. The primary synaptic center of olfactory processing, the insect antennal lobe (AL) and the olfactory bulb in vertebrates, is subdivided into synaptic glomeruli and monospecificity of ORN sensory input defines an evolutionary conserved glomerular feature [5].

The Drosophila AL consists of ∼50 glomeruli of stereotypical shape and position, which fits the estimated 50 ORN classes localized in the two olfactory sense organs, antenna and maxillary palp [1, 4, 6, 7, 8] (Figure 1a). Inside the glomerulus, ORNs make synapses with two major types of second-order interneurons, the projection neurons (PNs) and the local interneurons (LNs). Most PNs elaborate dendrites in only one of the 50 AL glomeruli, thereby transmitting ORN input with point-to-point correspondence to the high brain centers [9]. PNs extend axons through distinct tracts and acquire class-specific arborization patterns in the mushroom bodies and the lateral horns [8, 9]. By contrast, LNs form an extensive network of inhibitory and excitatory synaptic connections with both PNs and ORNs, and these interconnections play central roles in the processing of olfactory information [10, 11, 12].

Although the molecular and cellular organization of the insects and mammalian olfactory system is remarkably similar [5], the developmental control mechanisms underlying olfactory circuit formation are quite different. In mammals, sensory neurons stochastically select a single OR gene, which subsequently blocks the expression of a second receptor in a negative feedback mechanism [13, 14, 15]. In addition, the functional OR type localizes in growing ORN axons to determine their synaptic specificity in the olfactory brain center [16]. By contrast, receptor-to-neuron map in Drosophila is highly stereotyped and depends on the lineage-related genetic control mechanisms with no indication of a negative feedback control [17]. Furthermore, OR expression in developing sensory neurons starts after their axons have established class-specific connections in the brain, excluding a role of Drosophila ORs in neuronal wiring [4, 18, 19]. This raises the question of how a precise olfactory map can be established in an OR-independent fashion.

Here we discuss recent findings on the genetic control of sensory and synaptic specificity in the Drosophila olfactory system. Mutant studies have identified critical components in sensory neuron differentiation that ensures unique OR gene expression. A comprehensive cell lineage analysis showed that different developmental strategies are employed to specify the neuronal identity of ORN classes and PN/LN classes.

Section snippets

Specification of olfactory receptor neurons

The Drosophila antennae and the maxillary palps are covered by more than 450 olfactory sensilla, each of which contains a stereotypic combination of up to four different ORNs [8]. Three main morphological types of sensilla, concentrated at distinct antennal regions, can be distinguished [1, 8, 20]. Whereas basiconic and trichoid sensilla contain ORNs that express one of the 60 OR genes encoding seven-transmembrane G protein-coupled receptors (GPCRs) [20, 21, 22], the coeloconic sensilla contain

Development of olfactory receptor neuron connectivity

During Drosophila pupal development, newly specified ORNs send their axons in separate fascicles from the antennal epithelium towards the AL, in which PN dendrites have already established a coarse positional map [30]. ORN axons first project in distinct medial-lateral pathways along the periphery of the AL, before they converge into initial protoglomeruli [18]. Glomerulus maturation involves the class-specific assembly of ORN axons and PN dendrites into functional microcircuits, as well as the

Olfactory receptor gene choice

The mechanism underlying the specific expression of OR genes is not well understood. As the premature expression of an ectopic OR does not effect the endogenous receptor selection, a negative feedback mechanism to ensure the ‘One neuron–One receptor’ rule is absent in Drosophila [17]. Specification of OR identity rather seems to be linked to segregation of distinct cell fates in a lineage-related mechanism as described above. Studies on the organization of OR gene regulatory elements have

Specification of second-order interneurons

The AL contains synaptic connections between axons of 1300 ORNs and dendrites of roughly 200 PNs and 100 LNs [46•, 47]. In contrast to the ‘single class-single glomerulus’ segregation of sensory axons, the innervation of PN and LN dendrites in the AL is more heterogeneous (Figure 2a). Although the majority of PN classes limit their dendritic arborizations to a single glomerulus, recent systematic analysis of neuronal diversity in the AL revealed additional multiglomerular PNs [46] (Figure 2a).

Cellular interactions in PN–LN patterning

The initial targeting of PN dendrites precedes the arrival of pioneering ORN axons, indicating that the coarse glomerular map derives from complex cellular interactions among PN dendrites [30]. PN cell-body position in the three cell clusters does not predict the final locations of their dendrite projections [9, 50]. PN dendrite targeting to distinct glomeruli seems to occur in a step-wise fashion, in which outgrowing dendritic processes are initially positioned in a coarse map in the AL

Conclusions

Although recent studies have provided an almost complete morphological description of the hundreds of different neuronal cell types that constitute an olfactory map in the Drosophila brain, we are just beginning to understand the molecular mechanisms that provide each of these neurons with a unique cellular identity. Initially, sensory neurons and second-order target neurons in the brain become specified independently by cell-intrinsic determinants, followed by self-organizing patterning

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank C. Klämbt, P. Kain and members of the Hummel lab for helpful comments on the manuscript and apologize to all whose work we were not able to include. T.H. is supported by the DFG Heisenberg Program, the EMBO Young Investigator Program and the Schram Foundation.

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