The long and the short of it - a perspective on peptidergic regulation of circuits and behaviour.

Neuropeptides are the most diverse class of chemical modulators in nervous systems. They contribute to extensive modulation of circuit activity and have profound influences on animal physiology. Studies on invertebrate model organisms, including the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, have enabled the genetic manipulation of peptidergic signalling, contributing to an understanding of how neuropeptides pattern the output of neural circuits to underpin behavioural adaptation. Electrophysiological and pharmacological analyses of well-defined microcircuits, such as the crustacean stomatogastric ganglion, have provided detailed insights into neuropeptide functions at a cellular and circuit level. These approaches can be increasingly applied in the mammalian brain by focusing on circuits with a defined and identifiable sub-population of neurons. Functional analyses of neuropeptide systems have been underpinned by systematic studies to map peptidergic networks. Here, we review the general principles and mechanistic insights that have emerged from these studies. We also highlight some of the challenges that remain for furthering our understanding of the functional relevance of peptidergic modulation.

Drosophila Psidin regulates olfactory neuron number and axon targeting through two distinct molecular mechanisms.

The formation of neuronal circuits is a key process of development, laying foundations for behavior. The cellular mechanisms regulating circuit development are not fully understood. Here, we reveal Psidin as an intracellular regulator of Drosophila olfactory system formation. We show that Psidin is required in several classes of olfactory receptor neurons (ORNs) for survival and subsequently for axon guidance. During axon guidance, Psidin functions as an actin regulator and antagonist of Tropomyosin. Accordingly, Psidin-deficient primary neurons in culture display growth cones with significantly smaller lamellipodia. This lamellipodial phenotype, as well as the mistargeting defects in vivo, is suppressed by parallel removal of Tropomyosin. In contrast, Psidin functions as the noncatalytic subunit of the N-acetyltransferase complex B (NatB) to maintain the number of ORNs. Psidin physically binds the catalytic NatB subunit CG14222 (dNAA20) and functionally interacts with it in vivo. We define the dNAA20 interaction domain within Psidin and identify a conserved serine as a candidate for phosphorylation-mediated regulation of NatB complex formation. A phosphomimetic mutation of this serine showed severely reduced binding to dNAA20 in vitro. In vivo, it fully rescued the targeting defect but not the reduction in neuron numbers. In addition, we show that a different amino acid point mutation shows exactly the opposite effect by rescuing only the cell number but not the axon targeting defect. Together, our data suggest that Psidin plays two independent developmental roles via the acquisition of separate signaling pathways, both of which contribute to the formation of olfactory circuits.

A new Prospero and microRNA-279 pathway restricts CO2 receptor neuron formation.

CO(2) sensation represents an interesting example of nervous system and behavioral evolutionary divergence. The underlying molecular mechanisms, however, are not understood. Loss of microRNA-279 in Drosophila melanogaster leads to the formation of a CO(2) sensory system partly similar to the one of mosquitoes. Here, we show that a novel allele of the pleiotropic transcription factor Prospero resembles the miR-279 phenotype. We use a combination of genetics and in vitro and in vivo analysis to demonstrate that Pros participates in the regulation of miR-279 expression, and that reexpression of miR-279 rescues the pros CO(2) neuron phenotype. We identify common target molecules of miR-279 and Pros in bioinformatics analysis, and show that overexpression of the transcription factors Nerfin-1 and Escargot (Esg) is sufficient to induce formation of CO(2) neurons on maxillary palps. Our results suggest that Prospero restricts CO(2) neuron formation indirectly via miR-279 and directly by repressing the shared target molecules, Nerfin-1 and Esg, during olfactory system development. Given the important role of Pros in differentiation of the nervous system, we anticipate that miR-mediated signal tuning represents a powerful method for olfactory sensory system diversification during evolution.