Retrograde Gbb signaling through the Bmp type 2 receptor Wishful Thinking regulates systemic FMRFa expression in<i>Drosophila</i>

Marqués, Guillermo; Haerry, Theodore E; Crotty, M. Lisa; Xue, Mingshan; Zhang, Bing; O’Connor, Michael B.

doi:10.1242/dev.00772

Cited by 95 publications

(110 citation statements)

References 99 publications

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“…Similarly, while it is clear that CREB can be synthesised in dendrites 21 , the inherent difficulties in selectively abolishing the dendritic CREB pool have prevented a thorough elucidation of the exact role of dendritically-synthesised CREB in neuronal signalling. By selectively abolishing axonal CREB mRNA, the data presented here supports a nuclear role for extrasomatic pools of CREB.During development, axons encounter a variety of signals that affect multiple aspects of neuronal development, such as axonal elongation, branching, and pathfinding, as well as synaptogenesis and neuronal differentiation 9,46,47 . Increasing evidence suggests that many of these processes involve retrograde signals that affect gene transcription.…”

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confidence: 61%

Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

et al. 2008

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During development of the nervous system, axons and growth cones contain mRNAs, such as β-actin, cofilin, and RhoA, that are locally translated in response to guidance cues. Intra-axonal translation of these mRNAs results in local morphological responses, however other functions of intra-axonal mRNA translation remain unknown. Here we show that axons of developing mammalian neurons contain mRNA encoding the cAMP-responsive element (CRE)-binding protein (CREB). CREB is translated within axons in response to NGF and is retrogradely trafficked to the cell body. In neurons that are selectively deficient in axonal CREB transcripts, increases in nuclear pCREB, CRE-mediated transcription, and neuronal survival elicited by axonal application of NGF are abolished, indicating a signalling function for axonally-synthesised CREB. These studies identify a signalling role for axonally-derived CREB, and indicate that signaldependent synthesis and retrograde trafficking of transcription factors enables specific transcriptional responses to signalling events at distal axons.An important mechanism by which the protein composition at specific subcellular sites is regulated is by the precise intracellular targeting and translation of certain mRNAs 1 . This mechanism particularly evident in axons of developing neurons, which contain mRNAs, ribosomes, and other translational machinery 2 . Most known axonal mRNAs encode proteins that are involved in cytoskeletal regulation, and are involved in mediating the response to guidance cues [3][4][5] . Roles for axonal mRNA translation in other processes have not been established.One critical function of axons during development is to detect signals in the extracellular environment and to transduce these signals into changes in gene expression in the nucleus [6][7][8][9] . In developing sympathetic and sensory axons, growth cones detect nerve growth factor (NGF) synthesised by target cells, resulting in the generation of a retrograde signal that is conveyed to the soma that promotes neuronal survival 10 .Here we describe a role for axonal mRNA translation in the regulation of neuronal survival and nuclear transcription elicited by axonal application of NGF. We find NGF triggers axonal protein synthesis, which is required for NGF-mediated retrograde survival. A cDNA library prepared from the axons of developing sensory neurons reveals that CREB mRNA is an axonally-localised transcript. We find that CREB is selectively translated in axons in response to NGF and retrogradely trafficked to the cell body. Furthermore, selective 3 Correspondence should be addressed to S.R.J. (srj2003@med.cornell.edu). NIH Public Access Author ManuscriptNat Cell Biol. Author manuscript; available in PMC 2011 August 9. knockdown of axonal CREB mRNA reveals that axonally-synthesised CREB is required for NGF at axons to promote the accumulation of pCREB in the nucleus, transcription of a CRE-containing reporter gene, and neuronal survival. These data identify a role for axonally-synthesised CREB and identify a ...

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confidence: 61%

Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

et al. 2008

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“…Gbb is thought to function as a retrograde ligand in the neuromuscular junction (53). Gbb mutants have reduced larval neuromuscular junctions and diminished neurotransmission (54,55). Gbb is involved in proliferation and vein patterning in wing disk (52).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Molecular Basis of the Drosophila Mutations in Carboxypeptidase D

Sidyelyeva

Baker

Fricker

2006

Journal of Biological Chemistry

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Carboxypeptidase D (CPD) functions in the processing of proteins and peptides in the secretory pathway. Drosophila CPD is encoded by the silver gene (svr), which is differentially spliced to produce long transmembrane protein forms with three metallocarboxypeptidase (CP)-like domains and short soluble forms with a single CP domain. Many svr mutants have been reported, but the precise molecular defects have not been previously determined. In the present study, three mutant lines were characterized. svr Metallocarboxypeptidases (CPs)3 perform many physiological functions, ranging from the digestion of food to the biosynthesis of neuropeptides (1-10). CPs are divided into three subfamilies based on amino acid analysis: the A/B subfamily (1-3, 9), the N/E subfamily (4 -8, 10), and a recently discovered subfamily that includes Nna1 and related proteins but has not yet been demonstrated to have CP activity (11). Within each subfamily, the members show 35-60% amino acid sequence identity, but between subfamilies, there is only 15-25% amino acid sequence conservation. The A/B subfamily is primarily involved in protein digestion, either in the digestive track or elsewhere in the body. In contrast, the N/E subfamily plays more of a biosynthetic role by selectively removing specific residues from peptide processing intermediates, and this step often affects the biological properties of the substrate. In humans and mice, there are eight members of this N/E family, of which five show enzymatic activity (CPE, CPN, CPM, CPZ, and CPD); the remaining members of this subfamily (CPX1, CPX2, and AEBP-1/ACLP) are not active toward standard substrates (4 -8, 10, 12-15). In contrast, Drosophila contains only two members of this subfamily, one that has high homology to CPM and another that is a CPD homolog (16).CPD is unique among CPs in that it contains multiple CP-like domains, a transmembrane domain, and a short cytosolic tail (5). Humans, rats, mice, duck, and Drosophila CPD all contain three CP-like domains, of which the first two are enzymatically active and the third is missing key catalytic residues but still appears to retain the basic CP-like structure (16 -27). The functional significance of the three CP-like domains in CPD is not clear. One proposal is that the distinct pH optima of the first two domains enable CPD to be active throughout the secretory pathway, which ranges from neutral to acidic pH values (17, 28). In both duck and Drosophila, the first domain is more active at neutral pH, whereas the second domain is optimally active at pH 5-6 (16, 17, 28). Protein containing both domains together showed a broader pH optimum (17, 28).There are several known mutations for CPD in Drosophila that are collectively known as the silver, or svr, mutants based on the silvery body color of the viable mutants (27,29). In addition to the body color, the viable svr mutants have been reported to show altered wing shape and mating behavior in light (30, 31), although these results have not been adequately described in the literature....

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“…The expression of FMRF-amide (FMRFa)-like peptides in a subset of central peptidergic neurons, termed Tv neurons, is similarly dependent on Gbb retrograde signaling from neurohaemal organs innervated by these neurons (Allan et al, 2003;Marqués et al, 2003). Through a particularly elegant use of chimeric receptors, Marqués et al (2003) provide convincing data to indicate that Gbb acts via Wit and Tkv to specify FMRFa expression.…”

Section: Discussionmentioning

confidence: 99%

“…Through a particularly elegant use of chimeric receptors, Marqués et al (2003) provide convincing data to indicate that Gbb acts via Wit and Tkv to specify FMRFa expression. Chimeric receptors containing elements from both Wit and Sax were nonfunctional.…”

Section: Discussionmentioning

confidence: 99%

Synaptic Strengthening Mediated by Bone Morphogenetic Protein-Dependent Retrograde Signaling in theDrosophilaCNS

Baines¹

2004

J. Neurosci.

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Retrograde signaling is an essential component of synaptic development and physiology. Previous studies show that bone morphogenetic protein (BMP)-dependent retrograde signaling is required for the proper development of the neuromuscular junction (NMJ) in Drosophila. These studies, moreover, raised the significant possibility that the development of central motor circuitry might similarly be reliant on such signaling. To test this hypothesis, retrograde signaling between postsynaptic motoneurons and their presynaptic interneurons is examined. Postsynaptic expression of an adenylate cyclase encoded by rutabaga (rut), is sufficient to strengthen synaptic transmission at these identified central synapses. Results are presented to show that the underlying mechanism is dependent on BMP retrograde signaling. Thus, presynaptic expression of an activated TGF-␤ receptor, thickvien (tkv), or postsynaptic expression of a TGF-␤ ligand, glass-bottom boat ( gbb), is sufficient to phenocopy strengthening of synaptic transmission. In the absence of gbb, endogenous synaptic transmission is significantly weakened and, moreover, postsynaptic overexpression of rut is unable to potentiate synaptic function. Potentiation of presynaptic neurotransmitter release, mediated by increased postsynaptic expression of gbb, is dependent on normal cholinergic activity, indicative that either the secretion of this retrograde signal, or its transduction, is activity dependent. Thus, in addition to the development of the NMJ and expression of myoactive FMRFamide-like peptides in specific central neurons, the results of the present study indicate that this retrograde signaling cascade also integrates the development and function of central motor circuitry that controls movement in Drosophila larvae.

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Retrograde Gbb signaling through the Bmp type 2 receptor Wishful Thinking regulates systemic FMRFa expression inDrosophila

Cited by 95 publications

References 99 publications

Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

Characterization of the Molecular Basis of the Drosophila Mutations in Carboxypeptidase D

Synaptic Strengthening Mediated by Bone Morphogenetic Protein-Dependent Retrograde Signaling in theDrosophilaCNS

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