Trends in Neurosciences
Orchestrating development and function: retrograde BMP signaling in the Drosophila nervous system
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.
References (50)
Retrograde signaling by the neurotrophins follows a well-worn trk
Trends Neurosci.
(2002)Atypical neural messengers
Trends Neurosci.
(2001)- et al.
Retrograde signaling by endocannabinoids
Curr. Opin. Neurobiol.
(2002) The Drosophila BMP type II receptor wishful thinking regulates neuromuscular synapse morphology and function
Neuron
(2002)wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila
Neuron
(2002)Retrograde control of synaptic transmission by postsynaptic CaMKII at the Drosophila neuromuscular junction
Neuron
(2003)The BMP homolog Gbb provides a retrograde signal that regulates synaptic growth at the Drosophila neuromuscular junction
Neuron
(2003)- et al.
BMPs, Smads and metalloproteases: extracellular and intracellular modes of negative regulation
Curr. Opin. Genet. Dev.
(1998) BMP, Wnt and Hedgehog signals: how far can they go?
Curr. Opin. Cell Biol.
(2000)Specification of neuropeptide cell identity by the integration of retrograde BMP signaling and a combinatorial transcription factor code
Cell
(2003)
Developmental alteration and neuron-specific expression of bone morphogenetic protein-6 (BMP-6) mRNA in rodent brain
Brain Res. Mol. Brain Res.
Early development of the Drosophila neuromuscular junction: a model for studying neuronal networks in development
Int. Rev. Neurobiol.
Assembly and maturation of the Drosophila larval neuromuscular junction
Int. Rev. Neurobiol.
Genetic analysis of the mechanisms controlling target selection: complementary and combinatorial functions of netrins, semaphorins, and IgCAMs
Cell
Watching a synapse grow: noninvasive confocal imaging of synaptic growth in Drosophila
Neuron
Homeostatic control of presynaptic release is triggered by postsynaptic membrane depolarization
Neuron
Postsynaptic PKA controls quantal size and reveals a retrograde signal that regulates presynaptic transmitter release in Drosophila
Neuron
Genetic analysis of glutamate receptors in Drosophila reveals a retrograde signal regulating presynaptic transmitter release
Neuron
The Drosophila Wnt, wingless, provides an essential signal for pre- and postsynaptic differentiation
Cell
Highwire regulates synaptic growth in Drosophila
Neuron
Highwire, rpm-1, and futsch: balancing synaptic growth and stability
Neuron
New intracellular components of bone morphogenetic protein/Smad signaling cascades
FEBS Lett.
Location, location, location: a spatial view of neurotrophin signal transduction
Trends Neurosci.
Unrestricted synaptic growth in spinster – a late endosomal protein implicated in TGF-β-mediated synaptic growth regulation
Neuron
Spinsters, synaptic defects, and amaurotic idiocy
Neuron
Cited by (107)
The exocyst subunit Sec15 is critical for proper synaptic development and function at the Drosophila NMJ
2024, Molecular and Cellular NeuroscienceMadm/NRBP1 mediates synaptic maintenance and neurodegeneration-induced presynaptic homeostatic potentiation
2022, Cell ReportsCitation Excerpt :We next asked how presynaptic Madm controls synapse stability and growth. To identify relevant signaling pathways, we performed a trans-heterozygous genetic interaction assay with components of the two major growth promoting pathways at the larval NMJ, the transforming growth factor β (TGF-β)/BMP (Bone Morphogenic Protein), and the TOR signaling pathways (Figure S4A).36,37,38,39,40,41,42 Although we did not observe any significant interactions between Madm and components of the TGF-β/BMP pathway, trans-heterozygous combinations of Madm and TOR pathways members (TCS2/gigas; rheb) significantly impaired NMJ growth compared with control genotypes (Figure S4B).
Advances in next-generation sequencing technologies and functional investigation of candidate variants in neurological and behavioral disorders
2021, Encyclopedia of Behavioral Neuroscience: Second EditionSpecification of the Drosophila Orcokinin A neurons by combinatorial coding
2023, Cell and Tissue Research