InteractiveFly: GeneBrief

maverick: Biological Overview | References


Gene name - maverick

Synonyms -

Cytological map position - 4-0

Function - TGFβ family ligand

Keywords - GFR/Ret ligand - ancestor of GDNF - concentrated in the foregut - broad expression pattern suggests that the Ret/Gfrl signaling pathway could be permissive rather than instructive during stomatogastric nervous system precursor migration - neuromuscular junction glia release Maverick (Mav), which likely activates the muscle activin-type receptor Punt to potently modulate Gbb-dependent retrograde signaling and synaptic growth

Symbol - mav

FlyBase ID: FBgn0039914

Genetic map position - chr4:623,219-626,031

Classification - Transforming growth factor beta like domain

Cellular location - secreted



NCBI links: EntrezGene, Nucleotide Protein
BIOLOGICAL OVERVIEW

The RET receptor tyrosine kinase is crucial for the development of the enteric nervous system (ENS), acting as a receptor for Glial cell line-derived neurotrophic factor (GDNF) via GFR co-receptors. Drosophila has a well-conserved RET homolog (Ret) that has been proposed to function independently of the Gfr-like co-receptor (Gfrl). This study found that Ret is required for development of the stomatogastric (enteric) nervous system in both embryos and larvae, and its loss results in feeding defects. Live imaging analysis suggests that peristaltic waves are initiated but not propagated in mutant midguts. Examination of axons innervating the midgut reveals increased branching but the area covered by the branches is decreased. This phenotype can be rescued by Ret expression. Additionally, Gfrl shares the same ENS and feeding defects, suggesting that Ret and Gfrl might function together via a common ligand. This study identified the TGFβ family member Maverick (Mav) as a ligand for Gfrl and a Mav chromosomal deficiency displayed similar embryonic ENS defects. These results suggest that the Ret and Gfrl families co-evolved before the separation of invertebrate and vertebrate lineages (Myers, 2018)

The RET (rearranged during transfection) receptor tyrosine kinase is the leading susceptibility locus for Hirschsprung's disease (HSCR), a congenital lack of neurons in the distal regions of the digestive tract. HSCR arises due to the abnormal migration and survival of enteric neuron precursors derived from the neural crest, which has been classified as a neurocristopathy. RET is also found to have a role in kidney development and in a subset of neuroendocrine cancers. The ligands for RET are members of the Glial cell line-derived neurotrophic factor (GDNF) family, which act by binding to a GDNF family receptor (GFR) to activate intracellular RET signaling, or the Neural cell adhesion molecule (NCAM). GDNF is an important component of vertebrate brain development and maintenance, with clinical relevance to Parkinson's disease (Myers, 2018)

GDNF ligands appeared with the emergence of jawed fish and GFRs underwent a gene expansion at the same time. This expansion coincides with the appearance of the neural crest, a distinguishing structure for vertebrates. Homologs of the RET and GFR receptors are present in invertebrates but are thought to function independently of each other, with GFRs operating in conjunction with Fas2/NCAM rather than with a soluble ligan. In Drosophila, the RET gene (Ret) is expressed by enteric neurons and epithelial progenitor cells of the adult midgut and is required for homeostasis of these populations (Perea, 2017). In the Drosophila embryo, Ret is expressed in the developing stomatogastric nervous system (SNS), a population of cells that delaminate and migrate along the developing gut to form the enteric nervous system (ENS), and Ret is also expressed in the Malpighian tubules, the fly equivalent of the kidney. A previous study observed expression of Gfrl promoter fragments in the developing SNS, suggesting that Ret and Gfrl might function together in this tissue (Hernandez, 2015). Using CRISPR this study generated Drosophila Ret alleles and found defects in embryonic SNS formation and larval SNS function. These phenotypes led identification of the novel TGFβ family member Maverick (Mav) as an invertebrate GFR/Ret ligand and a candidate for the ancestor of GDNF. The results reveal remarkable similarities in the signaling mechanisms used to generate the insect SNS and the vertebrate ENS (Myers, 2018)

This study describes the effects of mutating the Ret gene in Drosophila and uncovered an evolutionarily conserved role in the development of the ENS. The incorrect positioning of SNS cells in the Drosophila embryo resembles hypoganglionic ENS phenotypes seen when RET is mutated in vertebrates. In HSCR, the most distal nerves of the digestive tract are affected. Likewise, in Ret mutant larvae the most distal nerves of the SNS, located on the midgut, have an altered anatomy and the larvae show defects in food ingestion. The phenotype resembles the neurotrophic effects of decreased serotonin or CNS dopamine signaling during midgut nerve formation, which also leads to increased axon branching and decreased feeding (Myers, 2018)

Although defects are visible in the embryonic SNS, there appear to be two separate lethal phases. Some first instar larvae display feeding defects and die. This is particularly evident in the original alleles that carry the background recessive lethal mutation, and the possibility is being investigated that the background lethal mutation specifically enhances the Ret mutations. Subsequent larval feeding defects often do not emerge until 2-4 days after hatching. Larvae with food in their guts can be observed foraging, suggesting that the larvae have problems with food ingestion. This is supported by observations of mutant larvae with food throughout their midguts, but with peristaltic defects in the anterior midgut. Initially a neurodegenerative defect similar to Wallerian degeneration was expected, but the axon defect was not suppressed by reducing dSarm activity. A model is currently favored in which initial SNS defects are amplified as the larva dramatically increases its mass several hundred fold. To keep pace with the expanding midgut, Ret may be required to promote axon growth, guidance, or be fulfilling a pro-synaptic role. These functions have been observed for RET and GDNF (Myers, 2018)

The midgut axon phenotype resembles defasciculation of the nerves and Gfrl genetically interacts with the fasciculation molecule Fas2, so Ret/Gfrl could potentially be modulating fasciculation as has been observed for other signaling systems. Alternatively, defasciculation may be a consequence of growth cones searching for sources of ligand, as proposed for Netrin and Bolwig's nerve. Decreased midgut innervation and function may provide negative feedback to upstream gut signaling, decreasing the ability to pass food through the pharynx and esophagus. The midgut axons may also be required to maintain communication with downstream enteroendocrine cells. An alternative hypothesis raised by the similarity of the Ret and Pink1 phenotypes is that the midgut neurons are running out of energy due to mitochondrial dysfunction (Myers, 2018).

This analysis enabled identification of the divergent TGFβ Mav as the elusive ligand for Drosophila Ret. The expression pattern of mav is consistent with a role in embryonic SNS development. Although the Mav ligand is concentrated in certain regions of the foregut and may create localized gradients, the broad expression pattern suggests that the Ret/Gfrl signaling pathway could be permissive rather than instructive during SNS precursor migration. Embryonic Ret signaling could primarily transduce a neurotrophic signal, and apoptosis has been observed in the migrating SNS precursors. In vertebrates, models in which GDNF/Ret signaling promotes proliferation rather than cell migration have been proposed to explain development of the nervous system. Experiments are underway to distinguish between these models in the fly. Although Gfrl expression has not yet been observed in the SNS, Gfrl could be acting in a soluble form or in trans. Gfrl promoter fragments continue to drive expression in the anterior midgut of the larvae in support of the trans model. Despite extensive sequence divergence in the extracellular domain of Ret, domain differences in GFRs and low homology of Mav to the GDNF family, the molecular logic of the protein complex appears preserved. In vertebrates, RET and GFR form a preassembled complex, and GDNF binds GFR to activate RET. Molecular data are strikingly similar, as this study found that Drosophila Ret and Gfrl can functionally interact in the absence of Mav, and that Mav interacts strongly with Gfrl, but only very weakly with Ret. In flies, Mav modulates synapse formation at the neuromuscular junction of body wall muscles. Ret is not expressed in body wall muscles , and Mav is likely to be signaling through activin/BMP type 1 receptors. A Mav homolog, Panda, has been found in the sea urchin Paracentrotus lividus, where it plays a role in dorsoventral axis formation and is also likely to be signaling through type 1 receptors. Mav and Panda both lack a key leucine residue, so their binding to type 1 receptors might be weaker than other ligands. Candidate Ret and Mav homologs have been found in Strongylocentrotus purpuratus, suggesting that Mav homologs might interact with both type 1 and Ret receptors in sea urchins (Myers, 2018).

Ret exhibits highly dynamic mRNA expression in the embryo. Ret is also expressed in adult midgut precursors at an earlier stage in development, as well as in discrete cells in the CNS, PNS and Malpighian tubules. mav mRNA is expressed weakly in the foregut primordium and at later stages in the pharynx, esophagus and proventriculus. Analysis of an epitope-tagged Mav expressed at endogenous levels indicates strong expression in the epithelial region from which the SNS precursor clusters delaminate and expansion to match the pattern of the mRNA, becoming concentrated near the sites at which the SNS neurons stop migrating (junction of the pharynx and esophagus, proventriculus). mav is also expressed in the epidermis and visceral mesoderm. Apart from promoter fragments driving reporters, Gfrl expression has not been observed in the SNS. Gfrl could therefore be expressed at low levels, or the protein might be acting in trans or in a soluble form. Gfrl promoter fragments continue to drive expression in the anterior midgut of the larvae (Myers, 2018).

Despite promiscuity in binding between TGFβ and their receptors in vertebrates, GDNF family members have not been reported to bind BMP/TGFβ receptors, suggesting that the ability to interact with more than one receptor was lost during evolution. The GDNF family of ligands, including GDNF, Neurturin, Artemin and Persephin, all appeared when fish gained jaws, as homologs cannot be identified in the published Agnatha sequences. GDNF ligands are distinguished by a highly conserved DLGLGY motif, part of one of two fingers that mediate binding to GFRα. This motif is not present in Mav or Panda. The change may have increased affinity or specificity for GFRs and additional changes might have prevented crosstalk with Activin/BMP type 1 receptors. Mav and Panda are similar to GDF-15, a TGFβ placed in the subfamily containing GDNF. GDF-15 is an inflammatory cytokine, and although it activates SMAD signaling, GDF-15 does not have an identified receptor. GDF-15 has GDNF-like neurotrophic activity for dopaminergic neurons, so it would be interesting to test GDF-15 for binding to GFRs (Myers, 2018).

The limited sequence data available suggest a model in which a divergent TGFβ acquired an ability to bind GFRs and activate Ret, which was followed by extensive co-evolution of the extracellular components. However, the downstream signaling pathways appear to be conserved, so the Ret SNS phenotypes open the door to invertebrate genetic analysis of this clinically important signaling pathway. Particularly exciting is the possibility of functional suppressor screens to identify mutations that could compensate for a lack of Ret signaling. Drosophila has already been used to identify genetic modifiers and a candidate drug to counteract oncogenic Ret signaling (Myers, 2018).

It is concluded Ret has an evolutionarily conserved role in the formation and function of the ENS. The GDNF signaling pathway has its origins in TGFβ signaling (Myers, 2018).

Integration of a retrograde signal during synapse formation by glia-secreted TGF-beta ligand

Glial cells are crucial regulators of synapse formation, elimination, and plasticity. In vitro studies have begun to identify glial-derived synaptogenic factors, but neuron-glia signaling events during synapse formation in vivo remain poorly defined. The coordinated development of pre- and postsynaptic compartments at the Drosophila neuromuscular junction (NMJ) depends on a muscle-secreted retrograde signal, the TGF-β/BMP Glass bottom boat (Gbb). Muscle-derived Gbb activates the TGF-β receptors Wishful thinking (Wit) and either Saxophone (Sax) or Thick veins (Tkv) in motor neurons. This induces phosphorylation of Mad (P-Mad) in motor neurons, its translocation into the nucleus with a co-Smad, and activation of transcriptional programs controlling presynaptic bouton growth. This study shows that NMJ glia release the TGF-β ligand Maverick (Mav), which likely activates the muscle activin-type receptor Punt to potently modulate Gbb-dependent retrograde signaling and synaptic growth. Loss of glial Mav results in strikingly reduced P-Mad at NMJs, decreased Gbb transcription in muscle, and in turn reduced muscle-to-motor neuron retrograde TGF-β/BMP signaling. It is proposed that by controlling Gbb release from muscle, glial cells fine tune the ability of motor neurons to extend new synaptic boutons in correlation to muscle growth. This work identifies a novel glia-derived synaptogenic factor by which glia modulate synapse formation in vivo (Fuentes-Medel, 2012).

Given the prominent role of glia and TGF-β signaling during synaptic bouton formation at the larval neuromuscular junction (NMJ), this study sought to determine whether ligands of the TGF-β superfamily are expressed in peripheral glia at the larval stage by real-time PCR. For this analysis, total RNA was isolated from segmental nerves in which the only cell bodies were peripheral glia and no neuronal RNAs were detected. This analysis revealed the presence of several transcripts for TGF-β ligands in glia, including Myoglianin (MYO), Dawdle (Daw), and Maverick (Mav). In contrast, Activin β (Actβ) transcripts were not detected in nerves. To explore a potential involvement of glia-derived TGF-β ligands in signaling synaptic development, RNAi transgenes targeting Daw, Mav, and MYO transcripts were expressed specifically in peripheral glia using the Gal4 driver Gli-Gal4 (rl82-Gal4). Downregulating Mav and Daw, but not MYO, in NMJ glia substantially reduced NMJ size, as determined by counting the number of synaptic boutons at the third-instar larval stage. In the case of Mav, the number of branches was also reduced (the number of branches in Mav-RNAi glia is 9.13 ± 0.70 compared with 17.0 ± 0.50 in controls) (Fuentes-Medel, 2012).

A classical readout of TGF-β pathway activation is Mad phosphorylation (P-Mad). At the Drosophila larval NMJ, TGF-β activation through P-Mad detection has been documented in both motor neuron nuclei and synaptic boutons of the NMJ. At synaptic boutons, P-Mad signal is organized into discrete puncta decorating synaptic boutons. Notably, downregulating Mav in peripheral glia with two different Mav-RNAi constructs targeting different regions of the Mav transcript virtually eliminated or severely reduced P-Mad immunoreactivity at synaptic sites. In contrast, downregulating MYO had no effect. A decrease in P-Mad signal was also observed by downregulating Daw in glia, but this effect was much weaker (Fuentes-Medel, 2012).

To assess whether Mav was exclusively required in glia for activation of TGF-β signaling, Mav-RNAi was expressed either muscles or motor neurons. However, no significant change was observed in synaptic P-Mad levels as a result of these manipulations. Thus, Mav is exclusively required in glia for activation of TGF-β signaling at synaptic sites. Further evidence for such requirement was obtained by examining the effect of overexpressing Mav in glia, which resulted in an increase of P-Mad signal intensity at the NMJ. Although there was no significant increase in the number of synaptic boutons at muscles 6 and 7 in parallel with the increase in synaptic P-Mad intensity, the number of boutons at muscle 4 was significantly increased. This increase was primarily due to an increase in the number of satellite boutons (small boutons emerging from normally sized synaptic boutons), which were significantly increased at muscles 6/7 and 4 (Fuentes-Medel, 2012).

In contrast to glia, downregulating Mav in motor neurons or muscles did not significantly change NMJ size. Interestingly, in vitro studies of the synaptogenic effects of Xenopus Schwann cells (SCs) led to the proposal that SC-derived TGF-β1 could promote synaptogenesis. However, the exact source of the synaptogenic signal was not clear, and whether TGF-β1 plays a role in the intact organism remains to be determined. These observations provide direct evidence indicating that a glia-derived TGF-β ligand can influence both TGF-β signaling and synaptic growth in vivo at the NMJ (Fuentes-Medel, 2012).

The requirement for peripheral glia in TGF-β pathway activation and synaptic bouton growth led to a prediction that peripheral glia should be capable of releasing Mav. An anti-Mav peptide antibody was generated and it was found labeled bright puncta within peripheral glial cells, consistent with the detection of Mav transcript in these cells. This labeling was specific, because it was almost completely eliminated by expressing Mav-RNAi in peripheral glia. To determine whether Mav could be released by peripheral glia, transgenic flies were generated expressing a green fluorescent protein (GFP)-tagged Mav transgene, and its expression was drivedn in NMJ glia with the rl82-Gal4 driver. This transgene was likely to be functional, because it behaved just like the untagged Mav transgene. In particular, expressing the GFP-tagged transgene in glia induced a significant increase in the number of boutons and satellite boutons (the number of boutons at muscle 4 is 63.3 ± 3.7 when Mav-GFP is expressed in glia, compared with 62.1 ± 3.1 when untagged Mav is expressed in glia, and 39.5 ± 2.0 in controls; the number of satellite boutons at muscle 4 is 19.5 ± 1.5 when Mav-GFP is expressed in glia, compared with 19.8 ± 1.1 when untagged Mav is expressed in glia and 5.5 ± 0.9 in controls. As with endogenous Mav, Mav-GFP became distributed in bright GFP puncta within glia in the segmental nerves. In addition, Mav-GFP was prominent at glial extensions that interact with the NMJ, showing that Mav-GFP is efficiently transported to these glial extensions. Notably, bright GFP puncta were also observed beyond the boundary of glial extensions, indicating that Mav-GFP could be released by peripheral glial cells. Close observation of the Mav-GFP puncta outside the glial membrane extensions revealed their localization in close association with both synaptic boutons and the postsynaptic junctional region of the muscle. In contrast, expressing Mav-GFP in neurons resulted in punctate and diffuse GFP staining within synaptic boutons, but no GFP signal was observed beyond the boundary of synaptic boutons, showing that Mav-GFP is likely not released from synaptic boutons. Similarly, expressing Mav-GFP in muscles resulted in very dim GFP signal in muscle cells, but this signal did not localize to the NMJ. Thus, Mav mRNA and protein are present in peripheral glia, glia can secrete transgenic Mav, and secreted Mav associates with synaptic boutons and muscles. Previous studies demonstrated that peripheral glial membrane extensions at the NMJ are dynamic, extending and retracting processes that become associated with synaptic boutons and muscles (Fuentes-Medel, 2009). Therefore, it is possible that glial membrane extensions might directly deposit Mav as they dynamically interact with boutons or muscles. Alternatively, glia-derived Mav may be released from these processes and diffuse to relatively distant sites (Fuentes-Medel, 2012).

The finding that glia can release Mav, and that glia-derived Mav is required for TGF-β signaling at synaptic sites, raised the question as to which cells (neurons or muscles) respond to Mav. The synaptic P-Mad signal is virtually absent when Mav is downregulated in glia. However, whether the P-Mad signal is pre- or postsynaptic has been a matter of debate. One study reported that synaptic P-Mad partially colocalized with the presynaptic active zone marker Bruchpilot (BRP) while it did not colocalize with Discs-large (DLG), suggesting that P-Mad is presynaptic. However, DLG is localized at the perisynaptic region within the pre- and postsynaptic compartments, and thus it is not expected to colocalize with the postsynaptic density. Another study reported that in wit mutants, the synaptic P-Mad signal was eliminated. Given the role of Wit receptors in activating TGF-β signaling in motor neurons, it was concluded that P-Mad was presynaptic. However, whether Wit is also expressed in muscles is unknown. In a third report, the synaptic P-Mad signal was found to completely colocalize with a tagged glutamate receptor GluRIIA transgene, which suggested a postsynaptic P-Mad localization. However, a comparison with endogenous GluRs was not done. To address this issue more directly, a strong hypomorphic mad mutant, mad12, over a mad deficiency chromosome was used and P-Mad labeling at the NMJ was examined. P-Mad immunoreactivity was completely eliminated in this mutant, providing direct evidence for the specificity of the P-Mad signal observed at the NMJ. Mad was then downregulated in either motor neurons or muscles by expressing Mad-RNAi and examined the intensity of the synaptic P-Mad signal. It was found that downregulating Mad in either neurons or muscles resulted in a significant decrease in P-Mad signal intensity, suggesting both a presynaptic and postsynaptic localization of P-Mad. Importantly, the number of synaptic boutons was significantly reduced by downregulation of Mad in either neurons or muscles, arguing strongly for a requirement for Mad function in both cell types (Fuentes-Medel, 2012).

The localization of P-Mad was examined in comparison with the endogenous localization of GluRIIA and BRP. Confirming previous reports with the GluRIIA transgene, it was found that synaptic P-Mad was always present within the boundaries of endogenous GluRIIA clusters. In contrast, only partial colocalization between BRP and P-Mad was observed, and the signals appeared juxtaposed. However, given that active zones and postsynaptic GluR clusters are apposed to each other in close proximity (<40 nm), it is noted that light microscopy alone cannot resolve this issue. Nevertheless, the finding that downregulating Mad in either muscles or neurons leads to both P-Mad reduction and NMJ growth defects is a strong indication that the signal is localized to both types of cells (Fuentes-Medel, 2012).

The finding that synaptic P-Mad can be attributed to muscles in addition to neurons, and that this signal is virtually eliminated by downregulating Mav in NMJ glia, provided compelling evidence that a TGF-β signal is activated in muscles as previously proposed. To confirm this finding, an additional reporter of TGF-β pathway activation, the transcription of daughters against dpp (Dad), an inhibitory Smad that antagonizes TGF-β signaling, was examined. Real-time PCR from larval body wall muscle RNA demonstrated that dad transcript was significantly decreased upon expression of Mav-RNAi in glia, providing additional support for a role of glia-derived Mav in activating TGF-β signaling in muscles (Fuentes-Medel, 2012).

It has been previously reported that the transcription of the Glass bottom boat (Gbb) retrograde ligand is also regulated by TGF-β pathway activation. Interestingly, downregulating Mav in glia resulted in a significant decrease in muscle gbb transcript levels. In contrast, cyclophilin control transcript levels were not affected. This observation raised the possibility that glial cells could modulate the intensity of the retrograde signal. To test this model, P-Mad levels were examined in the nuclei of motor neurons (a readout for retrograde TGF-β pathway activation). Expression of Mad-RNAi in motor neurons led to a drastic decrease in P-Mad immunoreactivity at motor neuron nuclei, demonstrating that the P-Mad signal at this site is specific. Most importantly, and consistent with the model, P-Mad immunoreactivity levels were significantly decreased in the nuclei of larval motor neurons when Mav-RNAi, but not MYO-RNAi or Daw-RNAi, was expressed in peripheral glia (Fuentes-Medel, 2012).

Finally, the levels of a TGF-β target gene in motor neurons, Trio, was also examined. Trio is a Rac-activating protein that contributes to cytoskeletal remodeling during synaptic growth. Previous studies demonstrated that upon activation of motor neuron TGF-β signaling by muscle Gbb, trio transcription is upregulated. Real-time PCR revealed that trio transcript levels were significantly reduced in RNA isolated from larval brains when Mav-RNAi was expressed in peripheral glia. In contrast, cyclophilin control transcript levels were unchanged by this manipulation. These results provide strong evidence that glia-derived Mav also modulates motor neuron TGF-β signaling. This modulation might occur through direct interaction of Mav with TGF-β receptors in motor neurons, or by regulating the levels of Gbb in muscles, leading to a change in Gbb release (Fuentes-Medel, 2012).

In support of the above model, it wass found that Mav function in NMJ development depended on Gbb. As noted, overexpressing Mav in glia results in a significant increase in the number of boutons. In contrast, no change in bouton number was observed in gbb/+ heterozygous larvae. Notably, the increase in bouton number observed upon overexpression of Mav in glia was completely suppressed in gbb/+ heterozygous larvae. These results point to a role of Gbb in mediating the response to glia-derived Mav during NMJ development (Fuentes-Medel, 2012).

Evidence was also found pointing to Punt as the likely receptor mediating the muscle response to glia-derived Mav. Downregulating Punt in muscle using two different RNAi lines targeted to different regions of Punt and the C57-Gal4 driver resulted in a substantial decrease in bouton number compared with the driver control. In addition, downregulating Punt in muscle decreased the levels of P-Mad immunoreactivity in motor neuron nuclei (Fuentes-Medel, 2012).

In summary, these studies provide direct in vivo evidence that glial cells secrete a TGF-β ligand, Mav, that influences the magnitude of Gbb-mediated muscle-to-motor neuron retrograde signaling. By controlling TGF-β signaling in both muscles and neurons, glial cells are well positioned to integrate the coordinated development of pre- and postsynaptic compartments (Fuentes-Medel, 2012).

It is interesting to note, however, that there could be partial redundancy between the two activin-type ligands, Mav and Daw, because glial knockdown of either leads to decreased NMJ growth and synaptic P-Mad, although the effect of Mav downregulation is substantially more severe. However, only glial knockdown of Mav affected levels of motor neuron nuclear P-Mad, suggesting that the pathways activated by the two ligands diverge. This divergence could result from the use of different receptor isoforms. For example, the activins Actβ and Daw can have different effects on the same tissues, as a result of differential interactions with alternative Baboon isoforms. Nevertheless, this work identifies a novel glial synaptogenic factor and provides compelling evidence for a critical role for glia in modulation of synapse assembly at the NMJ in vivo (Fuentes-Medel, 2012).

Identification of maverick, a novel member of the TGF-beta superfamily in Drosophila

The transforming growth factor-beta (TGF-beta) superfamily of structurally related ligands regulates essential signaling pathways that control many aspects of cell behavior in organisms across the phylogenetic spectrum. This study reports the identification of maverick (mav), a gene that encodes a new member of the TGF-beta superfamily in Drosophila. Phylogenetic analysis and sequence comparison suggest that Mav cannot be easily assigned to any one sub-family, since it is equally related to BMP, activin and TGF-beta ligands. mav maps to the fourth chromosome and is expressed throughout development. In situ hybridization experiments reveal the presence of maternally derived mav transcript in precellular blastoderm embryos. Later in development, mav is expressed in a dynamic pattern in the developing gut, both in endodermal and visceral mesodermal cells. In adult females, high levels of mav mRNA are present in late stage egg chambers (Nguyen, 2000).


REFERENCES

Search PubMed for articles about Drosophila

Fuentes-Medel, Y., Logan, M. A., Ashley, J., Ataman, B., Budnik, V. and Freeman, M. R. (2009). Glia and muscle sculpt neuromuscular arbors by engulfing destabilized synaptic boutons and shed presynaptic debris. PLoS Biol 7(8): e1000184. PubMed ID: 19707574

Fuentes-Medel, Y., Ashley, J., Barria, R., Maloney, R., Freeman, M. and Budnik, V. (2012). Integration of a retrograde signal during synapse formation by glia-secreted TGF-beta ligand. Curr Biol 22: 1831-1838. PubMed ID: 22959350

Hernandez, K., Myers, L. G., Bowser, M. and Kidd, T. (2015). Genetic tools for the analysis of Drosophila stomatogastric nervous system development. PLoS One 10(6): e0128290. PubMed ID: 26053861

Myers, L., Perera, H., Alvarado, M. G. and Kidd, T. (2018). The Drosophila Ret gene functions in the stomatogastric nervous system with the Maverick TGFbeta ligand and the Gfrl co-receptor. Development 145(3). PubMed ID: 29361562

Nguyen, M., Parker, L. and Arora, K. (2000). Identification of maverick, a novel member of the TGF-beta superfamily in Drosophila. Mech Dev 95(1-2): 201-206. PubMed ID: 10906462

Perea, D., Guiu, J., Hudry, B., Konstantinidou, C., Milona, A., Hadjieconomou, D., Carroll, T., Hoyer, N., Natarajan, D., Kallijarvi, J., Walker, J. A., Soba, P., Thapar, N., Burns, A. J., Jensen, K. B. and Miguel-Aliaga, I. (2017). Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia. EMBO J 36(20): 3029-3045. PubMed ID: 28899900


Biological Overview

date revised: 5 May 2018

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