Orchestrating development and function: retrograde BMP signaling in the Drosophila nervous system

https://doi.org/10.1016/j.tins.2004.01.004Get rights and content

Abstract

Recent work has shown that bone morphogenetic protein (BMP) growth factors regulate development of the larval neuromuscular junction (NMJ) of Drosophila. Intriguingly, the same BMP growth factors also influence the expression of circulating hormones that modulate the physiological properties of NMJs. Together, the results suggest that retrograde growth factor signaling by BMPs integrates neuromuscular development and function at both local and global levels in the animal.

Section snippets

Why Drosophila?

Drosophila has several advantages for studying synaptic development and function. Many Drosophila neurons are uniquely specified and individually identifiable cells. This makes it possible to study ‘identified’ synapses, such as those made by motoneurons onto body-wall muscle fibers [20]. The genes involved in synaptic development and function are readily identified through mutagenesis screens. Rapid progress is also aided by a completely sequenced Drosophila genome [21], by the availability of

Forward genetics implicates BMP signaling

The discovery of BMP signaling at the NMJ depended on ‘forward’ genetic mutagenesis screens. Using a fluorescent protein that accumulates at postsynaptic sites [28], members of the Goodman laboratory were able to visualize NMJs with altered morphology through the cuticle of undissected mutant larvae. Animals were also screened using ‘walking’ assays, to find mutants with locomotor defects [34]. Two particularly informative phenotypes were observed. The first involved larvae with abnormally

Open questions about BMP signaling at the NMJ

These observations raise several important issues. First, where does Gbb act when it influences NMJ development? Both Gbb and Wit are expressed by multiple cells in the CNS 9, 16, 17, raising the possibility that BMP signaling in the CNS is essential for normal NMJ development. However, there is reasonable evidence that Gbb does indeed act on BMP receptors in the periphery. The type-I BMP receptor Tkv is detected at presynaptic boutons 7, 10, 11, suggesting that the receptor apparatus is

Gbb and neuropeptide expression – closing the loop?

The actions of Gbb show how motoneuron structure and function can be regulated locally at each muscle fiber. NMJ function can also be regulated system-wide by means of circulating neuromodulatory peptides. For example, dFMRFamide (dFMRFa), a CNS-secreted neuropeptide, modulates NMJ neurotransmission and muscle force throughout the animal 46, 47. Intriguingly, researchers in the Thor, O'Connor and Zhang laboratories have found that dFMRFa expression is controlled by retrograde Gbb-dependent BMP

Concluding thoughts

It is tempting to speculate that the expression of Gbb in the NHO is under regulatory feedback control. Because the NHO is in communication with the circulating hemolymph, its cells could respond to endocrine signals that mirror the growth or metabolic state of the animal, providing a feedback loop that controls motor function (Figure 2). This hypothetical feedback loop from the periphery would regulate Gbb expression in Tv cells, and thus dFMRFa levels in the hemolymph.

Retrograde signaling via

Acknowledgements

We thank Guillermo Marqués, Brian McCabe, Scott Selleck, Corey Goodman, Stefan Thor and Michael O'Connor for providing prepublication material and comments. Haig Keshishian is supported by grants from the NIH and NSF.

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