InteractiveFly: GeneBrief

shriveled: Biological Overview | References

In the nervous system, reliable communication depends on the ability of neurons to adaptively remodel their synaptic structure and function in response to changes in neuronal activity. While neurons are the main drivers of synaptic plasticity, glial cells are increasingly recognized for their roles as active modulators. However, the underlying molecular mechanisms remain unclear. In this study, using Drosophila neuromuscular junction as a model system for a tripartite synapse, this study showed that peripheral glial cells collaborate with neurons at the NMJ to regulate activity-induced synaptic remodeling, in part through a protein called Shriveled (Shv). shv is an activator of integrin signaling previously shown to be released by neurons during intense stimulation at the fly NMJ to regulate activity-induced synaptic remodeling. This study demonstrate that Shv is also present in peripheral glia, and glial shv is both necessary and sufficient for synaptic remodeling. However, unlike neuronal shv, glial shv does not activate integrin signaling at the NMJ. Instead, it regulates synaptic plasticity in two ways: 1) maintaining the extracellular balance of neuronal shv proteins to regulate integrin signaling, and 2) controlling ambient extracellular glutamate concentration to regulate postsynaptic glutamate receptor abundance. Loss of glial cells showed the same phenotype as loss of shv in glia. Together, these results reveal that neurons and glial cells homeostatically regulate extracellular shv protein levels to control activity-induced synaptic remodeling. Additionally, peripheral glia maintains postsynaptic glutamate receptor abundance and contribute to activity-induced synaptic remodeling by regulating ambient glutamate concentration at the fly NMJ (Chang, 2025).

The nervous system is highly plastic, with the capacity to undergo dynamic alterations in structure and strength in response to changing stimuli and environments. This activity-induced synaptic remodeling process is highly conserved across species and plays crucial roles in circuit formation during development, as well as in stabilizing existing connections post-development. Synaptic remodeling represents a finely orchestrated process, with communications across both the pre- and postsynapses to allow the growth of new synapses, and the stabilization and strengthening of existing ones. While much of the research on synaptic plasticity has concentrated on interactions between presynaptic axon terminals and postsynaptic cells, most synapses are tripartite synapses, with glial cells as the third cell type. Beyond simply providing metabolic support, glial cells are increasingly recognized for their roles as active modulators of synaptic plasticity. However, the mechanisms by which glial cells and neurons collaborate to coordinate activity-induced synaptic remodeling are not well understood (Chang, 2025).

The Drosophila larval neuromuscular junction (NMJ) is a genetically tractable system and a tripartite glutamatergic synapse that serves as an excellent model system to investigate mechanisms underlying activity-induced synaptic remodeling by glial cells. The peripheral glial cells at the fly NMJ perform some of the key functions similar to mammalian glia, including controlling neuronal excitability and conduction velocity, recycling of neurotransmitters, and engulfing and clearing debris during damage to allow the growth of new boutons . They also release proteins such as transforming growth factor (TGF-β) to support synaptic growth, TNF-α (eiger) to influence neuronal survival, Wingless to regulate GluR clustering, and laminin to control animal locomotion. Nevertheless, the role of peripheral glia in regulating activity-induced stabilization and remodeling of the existing synapses at the NMJ remains unknown (Chang, 2025).

Previous studies on activity-induced synaptic remodeling at the fly NMJ demonstrated that neuronal activity leads to the enlargement of existing boutons, accompanied by increases in postsynaptic GluR abundance. Intense neuronal stimulation triggers the release of a protein called Shriveled (Shv) by presynaptic motoneurons, which activates βPS integrin bi-directionally to stimulate synaptic bouton enlargement and elevate GluR levels on the postsynaptic muscles. Consequently, shv mutants display defective post-tetanic potentiation (PTP), a form of functional synaptic plasticity similar to the early phase of long-term potentiation (LTP) seen in mammalian neurons. This study demonstrates that the Shv protein is also expressed in glial cells and is released extracellularly by peripheral glial cells. Glial shv not only regulates basal GluR clustering but is also required for activity-induced synaptic remodeling. It was further demonstrated that while glial shv is present extracellularly, it does not respond to neuronal activity, nor does it activate integrin signaling, unlike shv derived from neurons. Instead, glial shv contributes to synaptic plasticity regulation by modulating the levels of shv release from neurons and by controlling the levels of ambient glutamate concentration. Restoring ambient glutamate concentration could correct basal GluR abundance and defective synaptic plasticity caused by the loss of glial cells. These results further reveal that regulation of ambient extracellular glutamate concentration by glia is an important mechanism contributing to synaptic plasticity regulation (Chang, 2025).

This study shows that the peripheral glial cells at the Drosophila NMJ play an important role in regulating synaptic plasticity. Neurons and glia jointly orchestrate activity-induced synaptic remodeling at the NMJ, with shv playing a pivotal role. While neurons release shv in an activity-dependent manner to regulate synaptic remodeling through integrin signaling, release of shv by peripheral glial cells does not rely on neuronal activity and does not activate integrin signaling. Instead, glial shv influences activity-induced synaptic remodeling by keeping the levels of shv released by neurons in check and controlling ambient extracellular glutamate levels (Chang, 2025).

These data suggest that one mechanism underlying activity-induced synaptic remodeling by glia is through indirect control of shv release from neurons, thereby maintaining minimal integrin signaling under ambient conditions. It is propose that this low baseline integrin signaling enables neurons to respond with high sensitivity to enhanced integrin activation by shv release from neurons following neuronal activity, leading to rapid synaptic remodeling. Conversely, knocking down shv in glia removes this suppression, resulting in increased shv release from neurons, higher basal integrin signaling, GluR levels, and pathway saturation, thereby inhibiting activity-induced synaptic remodeling. Supporting this, overexpression of shv in neurons elevated basal pFAK and abolished synaptic plasticity. These findings also raise several intriguing questions, including how neurons and glia distinguish different sources of shv, and how they sense and communicate this information to regulate extracellular shv levels from different cells. Based on western blot analyses of adult heads and larval brains showing that shv is present as a single band, the functional differences in neuronal or glial shv are not likely due to the presence of different isoforms. Consistent with this, FlyBase also suggests that shv encodes a single isoform. However, while no obvious post-translational modifications was detected when shv protein was expressed in neurons or glia, the possibility cannot be excluded that different cell types process shv differently through post-transcriptional or post-translational mechanisms. Notably, shv is predicted to undergo A-to-I RNA editing, including an editing site in the coding region, which will result in a single amino acid change. Given that ADAR, the editing enzyme, is enriched in neurons and absent from glia, it is possible that such cell-specific editing could contribute to functional differences. It will be interesting to investigate this in the future (Chang, 2025).

This study found that another main function of glial shv is to regulate ambient extracellular glutamate concentration. Overexpression of shv elevated ambient glutamate levels at the synapse measured using a genetically encoded glutamate sensor, whereas knockdown of shv in glia reduced its level. Furthermore, ablating glia recapitulated the phenotypes of shv knockdown in glia, and transiently restoring extracellular ambient glutamate concentration efficiently rescued synaptic plasticity. Based on reports that it has been shown that the Drosophila larval NMJ maintains a surprisingly high ambient extracellular glutamate concentration, with an average in the range of 1–2 mM. How shv regulates extracellular glutamate concentration remains to be explored, but a likely mechanism is by affecting the levels or functions of the cystine/glutamate (Cx-T), which imports cystine and exports glutamate into the extracellular matrix. While shv has been shown to activate integrin, it encodes a homolog of the mammalian DNAJB11 protein, which functions as a molecular chaperone vital for proper protein folding in the endoplasmic reticulum. shv thus could potentially be required for the proper folding and the function of the Cx-T, which is located on glial cell membrane at the fly NMJ. Aligned with this, mutations in Cx-T also resulted in elevated basal GluR levels at the fly NMJ. Future studies examining the functional interactions between Cx-T and shv will shed light on mechanisms for shv-dependent regulation of ambient extracellular glutamate levels at the NMJ (Chang, 2025).

How does extracellular glutamate regulate GluR levels and synaptic plasticity? Changes in glutamate levels have been shown to directly impact neurotransmission, glutamate receptor activity, and influence GluR clustering by internalizing the desensitized GluR. This study has also shown that basal GluR level is homeostatically regulated by extracellular glutamate concentration. It is plausible that a high extracellular glutamate concentration enables the NMJ to maintain a reserved pool of GluRs that can be readily mobilized to the surface upon neuronal activity. Additionally, activation of GluR and downstream signaling pathways could trigger local protein translation machineries to prime the synapses to respond rapidly to changes in neuronal activity. Future studies examining intracellular mechanisms controlling activity-induced GluR increases will lead to better insights on synaptic plasticity regulation (Chang, 2025).

Activity-Induced Synaptic Structural Modifications by an Activator of Integrin Signaling at the Drosophila Neuromuscular Junction

Activity-induced synaptic structural modification is crucial for neural development and synaptic plasticity, but the molecular players involved in this process are not well defined. This paper reports that a protein named Shriveled (Shv) regulates synaptic growth and activity-dependent synaptic remodeling at the Drosophila neuromuscular junction. Depletion of shv causes synaptic overgrowth and an accumulation of immature boutons. shv physically and genetically interacts with betaPS integrin. Furthermore, shv is secreted during intense, but not mild, neuronal activity to acutely activate integrin signaling, induce synaptic bouton enlargement, and increase postsynaptic glutamate receptor abundance. Consequently, loss of shv prevents activity-induced synapse maturation and abolishes post-tetanic potentiation, a form of synaptic plasticity. These data identify shv as a novel trans-synaptic signal secreted upon intense neuronal activity to promote synapse remodeling through integrin receptor signaling (Lee, 2017).

This study shows that Shv is a novel protein secreted at the Drosophila NMJ. Shv is required during synaptic development to maintain normal synaptic growth and is released upon intense neuronal stimulation to acutely promote synapse maturation. It was further demonstrated that activity-induced release of Shv by neurons activates integrin signaling bidirectionally, induces bouton enlargement, and increases postsynaptic glutamate receptor abundance. Moreover, Shv is required to achieve synaptic augmentation and maintain potentiation following tetanic stimulation. These data thus suggest that trans-synaptic Shv released in response to strong neuronal activity acts as a molecular cue that triggers activity-induced synaptic structural modifications and synapse maturation through integrin activation (Lee, 2017).

These data reveal that presynaptically secreted Shv plays an important modulatory role in maintaining normal synaptic growth during development. Shv is specifically targeted to the synapse by neurons and released at low levels in the vicinity of synaptic terminals as shown by both immunostaining with Shv antibody and Shv-GFP fusion protein puncta. Furthermore, the secretion of Shv from the synapse is essential in restraining synaptic growth and promoting synapse maturation, since only the full-length Shv rescued the synaptic overgrowth and ghost bouton phenotypes of shv¹, whereas deleting the signal peptide of Shv did not. Previous studies have suggested that ghost boutons are newly formed, undifferentiated boutons in the process of maturing into functional boutons with postsynaptic glutamate receptors. The observations that shv¹ mutants have more synaptic boutons and ghost boutons suggest that presynaptically released Shv is not required for new bouton formation but rather restricts synaptic growth during development (Lee, 2017).

The low amounts of Shv present extracellularly likely activate βPS integrin signaling both presynaptically and postsynaptically to modulate synaptic growth. This is supported by previous work showing that activation of &betalPS integrin receptors by Shv in S2 cells, data that Shv can biochemically and genetically interact with βPS integrin to regulate synaptic growth, and that presynaptic knockdown of Shv significantly reduced pFAK levels in both presynaptic terminals and postsynaptic muscle. It is thus envisioned that Shv, once released at presynaptic terminals, is a trans-synaptic molecule that acts on βPS integrin receptors bidirectionally to affect synaptic growth through signaling pathways downstream of βPS integrin receptors. As there are multiple integrin ligands shown to affect synaptic growth and different integrin receptors at the NMJ, it is likely that Shv acts in concert with other integrin ligands to coordinate and optimize integrin activation and synaptic growth during development (Lee, 2017).

Although the involvement of integrin in synaptic growth and plasticity has been studied extensively, the identity of an extracellular ligand that modulates integrin signaling in response to synaptic activity remains to be elucidated. Excitingly, this study found that persistent synaptic activity or high-frequency stimulation induced the release of Shv, which led to a robust increase in pFAK level and synaptic bouton enlargement, a process normally associated with synaptic maturation. Furthermore, the incubation of purified Shv protein in dissected larval NMJ elevated the levels of pFAK and enlarged the size of synaptic boutons, while the mutant ShvLNV that cannot interact with βPS failed to elicit such changes. These results suggest that the extracellular presence of Shv is an instructive cue that is sufficient to acutely activate integrin signaling and induce synaptic structural modification. Moreover, the finding that the absence of Shv failed to elicit multiple phases of activity-induced synaptic plasticity, including initial augmentation during tetanus and PTP, supports the claim that Shv is required for synaptic plasticity (Lee, 2017).

To date, aside from Shv, laminin A is the only known integrin ligand with its release regulated in an activity-dependent manner at the Drosophila NMJ. However, laminin release by postsynaptic muscles is instead downregulated by synaptic activity and crawling, resulting in reduced pFAK through its retrograde action on presynaptically expressed βν integrin receptors. This study found that the release of Shv is stimulated by strong synaptic activity and acts independently of βνν integrin receptors. Interestingly, this study also found that the spaced potassium depolarization paradigm, which has been shown to induce new bouton formation and synaptic growth through the release of Wingless (Wg), did not trigger Shv release or elevate pFAK at the NMJ. Furthermore, this study found that while new bouton formation was blocked by transcription or translational inhibitors similar to those in previous reports, bouton maturation in the form of bouton enlargement and increase in glutamate receptor abundance was not affected. Together, these data support a model in which neurons activate different programs to differentially modulate synaptic growth and maturation in response to different synaptic demands (Lee, 2017).

Mild or patterned neuronal activity is proposed to trigger release of factors such as Wg and downregulates laminin release from muscles to initially promote synaptic growth and allow synaptic expansion (increase the number of boutons); persistent or intense synaptic activity then leads to the release of Shv from neurons to activate βPS integrin signaling bidirectionally to promote local synapse maturation. By selectively reducing presynaptic or postsynaptic βPS integrin receptors, presynaptic βPS signaling is absolutely required for bouton enlargement following neuronal activity, whereas postsynaptic βPS activation is required for the activity-induced increase in glutamate receptor abundance. Activation of βPS integrin signaling may lead to local synaptic enlargement in bouton size by promoting actin branching, which has been associated with growth in the size of boutons. The exact mechanism for how activation of βPS integrin leads to an increase in glutamate receptor abundance at the Drosophila NMJ is not clear, but mutations that reduce the levels of βPS integrin have also been shown to diminish glutamate receptor levels. Secreted extracellular protein such as Mind-the-gap, which has been suggested to recruit integrin receptor to the synaptic cleft, also affects synaptic localization of glutamate receptor clusters. Furthermore, PS integrin receptors have been reported to associate with Discs large, Fasciclin II cell adhesion molecule, and CaMKII, which are known to affect synaptic glutamate receptor assembly and anchoring. Understanding the downstream mechanism by which Shv-dependent integrin activation modulates the localization of glutamate receptor to promote the stability of synaptic structure during synaptic remodeling remains an interesting area to study in the future. It will also be particularly interesting to elucidate how neuronal activity triggers Shv release. As a robust neuronal circuitry depends on the ability of neurons to dynamically adjust synaptic strength and modify synaptic structure in response to synaptic demand, elucidating how Shv functions in activity-induced synaptic plasticity has implications for understanding mechanisms underlying cognition and psychiatric disorders (Lee, 2017).

Maintenance of Stem Cell Niche Integrity by a Novel Activator of Integrin Signaling

Stem cells depend critically on the surrounding microenvironment, or niche, for their maintenance and self-renewal. While much is known about how the niche regulates stem cell self-renewal and differentiation, mechanisms for how the niche is maintained over time are not well understood. At the apical tip of the Drosophila testes, germline stem cells (GSCs) and somatic stem cells share a common niche formed by hub cells. This study demonstrated that a novel protein named Shriveled (Shv) is necessary for the maintenance of hub/niche integrity. Depletion of shv protein results in age-dependent deterioration of the hub structure and loss of GSCs, whereas upregulation of shv preserves the niche during aging. shv is a secreted protein that modulates DE-cadherin levels through extracellular activation of integrin signaling. This work identifies shv as a novel activator of integrin signaling and suggests a new integration model in which crosstalk between integrin and DE-cadherin in niche cells promote their own preservation by maintaining the niche architecture (Lee, 2016).

Functions of Shriveled orthologs

Exosomal DNAJB11 promotes the development of pancreatic cancer by modulating the EGFR/MAPK pathway

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with invasive and metastatic characteristics and poor prognosis. Intracellular protein homeostasis is associated with invasion and metastasis of pancreatic cancer, but the specific molecular mechanism remains unclear. Previous studies have revealed that DNAJB11, a key protein in protein homeostasis, is secreted by exosomes in the supernatant of dissociated pancreatic cancer cells with high metastasis. The results from transcriptome sequencing and co-immunoprecipitation (Co-IP)-based liquid chromatography with tandem mass spectrometry (LC-MS/MS) showed that depletion of DNAJB11 levels could increase HSPA5 expression and induce endoplasmic reticulum stress through the PRKR-like endoplasmic reticulum kinase signaling pathway in pancreatic cancer cells. Furthermore, exosomal DNAJB11 promoted cell development of PC cells in vitro and in vivo. In addition, exosomal DNAJB11 could regulate the expression of EGFR and activate the downstream MAPK signaling pathway. Clinical blood samples were collected to evaluate the potential of exosome DNAJB11 as a diagnostic biomarker and therapeutic target for the treatment of pancreatic cancer. This study could provide a new theoretical basis and potential molecular targets for the treatment of pancreatic cancer (Liu, 2022).

Search PubMed for articles about Drosophila Shriveled

Chang, Y. C., Peng, Y. J., Lee, J. Y., Wen, A., Chang, K. T. (2025). Peripheral glia and neurons jointly regulate activity-induced synaptic remodeling at the Drosophila neuromuscular junction. bioRxiv, PubMed ID: 39005352

Lee, J. Y., Chen, J. Y., Shaw, J. L., Chang, K. T. (2016). Maintenance of Stem Cell Niche Integrity by a Novel Activator of Integrin Signaling. PLoS Genet, 12(5):e1006043 PubMed ID: 27191715

Lee, J. Y., Geng, J., Lee, J., Wang, A. R., Chang, K. T. (2017). Activity-Induced Synaptic Structural Modifications by an Activator of Integrin Signaling at the Drosophila Neuromuscular Junction. J Neurosci, 37(12):3246-3263 PubMed ID: 28219985

Liu, P., Zu, F., Chen, H., Yin, X., Tan, X. (2022). Exosomal DNAJB11 promotes the development of pancreatic cancer by modulating the EGFR/MAPK pathway. Cell Mol Biol Lett, 27(1):87 PubMed ID: 36209075

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