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Stetak A et al. (2011) Dev Biol "The C. elegans MAGI-1 protein is a novel component of cell junctions that is required for junctional compartmentalization."

Stetak A, Hajnal A

[

Dev Biol,

2011]

Cell junctions are essential to maintain polarity and tissue integrity. Epithelial cell junctions are composed of distinct sub-compartments that together ensure the strong adhesion between neighboring cells. In Caenorhabditis elegans epithelia, the apical junction (CeAJ) forms a single electron-dense structure, but at the molecular level it is composed of two sub-compartments that function redundantly and localize independently as two distinct but adjacent circumferential rings on the lateral plasma membrane. While investigating the role of the multi PDZ-domain containing protein MAGI-1 during C. elegans epidermal morphogenesis, we found that MAGI-1 localizes apical to both the Cadherin/Catenin (CCC) and AJM-1/DLG-1 (DAC) containing sub-domains. Removal of MAGI-1 function causes a loss of junctional compartmentalization along the lateral membrane and reduces the overall robustness of cell-cell adhesion mediated by either type of cell junctions. Our results suggest that MAGI-1 functions as an "organizer" that ensures the correct segregation of different cell adhesion complexes into distinct domains along the lateral plasma membrane. Thus, the formation of stable junctions requires the proper distribution of the CCC and DAC adhesion protein complexes along the lateral plasma membrane.

Stetak A et al. (2009) PLoS One "Neuron-specific regulation of associative learning and memory by MAGI-1 in C. elegans."

Hajnal A, Maricq AV, Horndli F, van den Heuvel S, Stetak A

[

PLoS One,

2009]

BACKGROUND: Identifying the molecular mechanisms and neural circuits that control learning and memory are major challenges in neuroscience. Mammalian MAGI/S-SCAM is a multi-PDZ domain synaptic scaffolding protein that interacts with a number of postsynaptic signaling proteins and is thereby thought to regulate synaptic plasticity [1], [2], [3]. PRINCIPAL FINDINGS: While investigating the behavioral defects of C. elegans nematodes carrying a mutation in the single MAGI ortholog magi-1, we have identified specific neurons that require MAGI-1 function for different aspects of associative learning and memory. Various sensory stimuli and a food deprivation signal are associated in RIA interneurons during learning, while additional expression of MAGI-1 in glutamatergic AVA, AVD and possibly AVE interneurons is required for efficient memory consolidation, i.e. the ability to retain the conditioned changes in behavior over time. During associative learning, MAGI-1 in RIA neurons controls in a cell non-autonomous fashion the dynamic remodeling of AVA, AVD and AVE synapses containing the ionotropic glutamate receptor (iGluR) GLR-1 [4]. During memory consolidation, however, MAGI-1 controls GLR-1 clustering in AVA and AVD interneurons cell-autonomously and depends on the ability to interact with the beta-catenin HMP-2. SIGNIFICANCE: Together, these results indicate that different aspects of associative learning and memory in C. elegans are likely carried out by distinct subsets of interneurons. The synaptic scaffolding protein MAGI-1 plays a critical role in these processes in part by regulating the clustering of iGluRs at synapses.

Stetak A et al. (2008) Dev Biol "Tissue-specific functions of the Caenorhabditis elegans p120 Ras GTPase activating protein GAP-3."

Gutierrez P, Hajnal A, Stetak A

[

Dev Biol,

2008]

All metazoan genomes encode multiple RAS GTPase activating proteins (RasGAPs) that negatively regulate the conserved RAS/MAPK signaling pathway. In mammals, several RasGAPs exhibit tumor suppressor activity by preventing excess RAS signal transduction. We have identified gap-3 as the to date missing Caenorhabditiselegans member of the p120 RasGAP family. By studying the genetic interaction of gap-3 with the two previously identified RasGAPs gap-1 and gap-2, we find that different combinations of RasGAPs are used to repress LET-60 RAS signaling depending on the cellular context. GAP-3 is the predominant negative regulator of RAS during meiotic progression of the germ cells, while GAP-1 is the key inhibitor of RAS during vulval induction. In other tissues such as the sex myoblasts or the chemosensory neurons, all three RasGAPs act in concert. The C. elegans RasGAPs have thus undergone partial specialization after gene duplication to allow the differential regulation of the RAS/MAPK signaling pathway in different cell types. A similar tissue specialization of the human tumor suppressor genes may explain the strong bias in the type of cancer they promote when mutated.

Stetak A et al. (2006) EMBO J "Cell fate-specific regulation of EGF receptor trafficking during Caenorhabditis elegans vulval development."

Hoier EF, Stetak A, Cassata G, Di Fiore PP, Hajnal A, Croce A

[

EMBO J,

2006]

By controlling the subcellular localization of growth factor receptors, cells can modulate the activity of intracellular signal transduction pathways. During Caenorhabditis elegans vulval development, a ternary complex consisting of the LIN-7, LIN-2 and LIN-10 PDZ domain proteins localizes the epidermal growth factor receptor (EGFR) to the basolateral compartment of the vulval precursor cells (VPCs) to allow efficient receptor activation by the inductive EGF signal from the anchor cell. We have identified EGFR substrate protein-8 (EPS-8) as a novel component of the EGFR localization complex that links receptor trafficking to cell fate specification. EPS-8 expression is upregulated in the primary VPCs, where it creates a positive feedback loop in the EGFR/RAS/MAPK pathway. The membrane-associated guanylate kinase LIN-2 recruits EPS-8 into the receptor localization complex to retain the EGFR on the basolateral plasma membrane, and thus allow maximal receptor activation in the primary cell lineage. Low levels of EPS-8 in the neighboring secondary VPCs result in the rapid degradation of the EGFR, allowing these cells to adopt the secondary cell fate. Extracellular signals thus regulate EGFR trafficking in a cell type-specific manner to control pattern formation during organogenesis.

Stetak AL et al. (2024) J Neurosci "A necessary role for PKC-2 and TPA-1 in olfactory memory and synaptic AMPAR trafficking in C. elegans."

Grenal T, Stetak AL, Hoerndli FJ, Doser RL, Lenninger Z, Knight KM

[

J Neurosci,

2024]

Protein Kinase C functions are essential for synaptic plasticity, learning and memory. However, the roles of specific members of the PKC family in synaptic function, learning and memory, are poorly understood. Here, we investigated the role of individual PKC homologs for synaptic plasticity in C. elegans and found a differential role for pkc-2 and tpa-1, but not pkc-1 and pkc-3 in associative olfactory learning and memory. More specifically we show that PKC-2 is essential for associative learning and TPA-1 for short-term associative memory. Using endogenous labeling and cell specific rescues we show that TPA-1 and PKC-2 are required in AVA for their functions. Previous studies demonstrated that olfactory learning and memory in C. elegans is tied to proper synaptic content and trafficking of AMPA type ionotropic glutamate receptor homologue GLR-1 in the AVA command interneurons. Therefore, we quantified synaptic content, transport, and delivery of GLR-1 in AVA and showed that loss of pkc-2 and tpa-1 leads to decreased transport and delivery but only subtle decrease in GLR-1 levels at synapses. AVA specific expression of both PKC-2 and TPA-1 rescued these defects. Finally, genetic epistasis showed that PKC-2 and TPA-1 likely act in the same pathway to control GLR-1 transport and delivery, while regulating different aspects of olfactory learning and short-term associative memory. Thus, our data tie together cell specific functions of 2 PKCs to neuronal and behavioral outcomes in C. elegans, enabling comparative approaches to understand the evolutionarily conserved role of PKC in synaptic plasticity, learning and memory.Significance Statement The Protein Kinase C family of kinases are essential signaling elements of synaptic plasticity. However, how different members interact to contribute to learning and memory and how this relates to cellular functions is technically challenging in vertebrate models. Here using C. elegans, we describe an approach combining behavior and cellular analysis for TPA-1 and PKC-2, one novel and one classical PKC isoform. Our findings show that changes in learning and memory due to loss of TPA-1 and PKC-2 can be related to changes in the dynamics of synaptic AMPA receptors. Thus, our approach using C. elegans offers the opportunity to better understand how the molecular functions of PKCs relate to their effect on learning and memory.

Gyurko MD et al. (2015) Sci Rep "Distinct roles of the RasGAP family proteins in C. elegans associative learning and memory."

Stetak A, Csermely P, Soti C, Gyurko MD

[

Sci Rep,

2015]

The Ras GTPase activating proteins (RasGAPs) are regulators of the conserved Ras/MAPK pathway. Various roles of some of the RasGAPs in learning and memory have been reported in different model systems, yet, there is no comprehensive study to characterize all gap genes in any organism. Here, using reverse genetics and neurobehavioural tests, we studied the role of all known genes of the rasgap family in C. elegans in associative learning and memory. We demonstrated that their proteins are implicated in different parts of the learning and memory processes. We show that gap-1 contribute redundantly with gap-3 to the chemosensation of volatile compounds, gap-1 plays a major role in associative learning, while gap-2 and gap-3 are predominantly required for short- and long-term associative memory. Our results also suggest that the C. elegans Ras orthologue let-60 is involved in multiple processes during learning and memory. Thus, we show that the different classes of RasGAP proteins are all involved in cognitive function and their complex interplay ensures the proper formation and storage of novel information in C. elegans.

Pellegrino MW et al. (2009) Dev Biol "The conserved zinc finger protein VAB-23 is an essential regulator of epidermal morphogenesis in Caenorhabditis elegans."

Stetak A, Pellegrino MW, Hajnal A, Gasser RB, Sprenger F

[

Dev Biol,

2009]

Caenorhabditis elegans is an excellent model to observe cell movements and shape changes during the morphogenesis of the egg-shaped embryo into an elongated tube-like larva. Although much is known about the structural determinants involved in epidermal morphogenesis, relatively little is known about the transcriptional and post-transcriptional regulatory networks involved. Here, we describe the identification and functional characterization of the novel nuclear protein VAB-23, which belongs to a conserved protein family found in all metazoans. C. elegans VAB-23 is essential for ventral closure and elongation of the embryo. Time-lapse analysis indicates that VAB-23 is required for the formation of proper cell contacts between contralateral pairs of ventral epidermal cells. Tissue-specific rescue experiments reveal a function of VAB-23 in ventral neuroblasts that control the enclosure of the embryo by the overlaying epidermal cells. Finally, we provide evidence suggesting a role of VAB-23 in post-transcriptional gene regulation. We thus propose that VAB-23 regulates the expression of multiple secreted guidance cues in ventral neuroblasts that direct the migration of the overlaying epidermal cells. Members of the VAB-23 family may perform similar functions during morphogenesis in other metazoans.

Veljkovic E et al. (2004) J Biol Chem "Aromatic amino acid transporter AAT-9 of Caenorhabditis elegans localizes to neurons and muscle cells."

Forster I, Skelly PJ, Bacconi A, Hajnal A, Verrey F, Shoemaker CB, Veljkovic E, Stetak A, Stasiuk S

[

J Biol Chem,

2004]

The C. elegans genome encodes nine homologues of mammalian glycoprotein-associated amino acid transporters. Two of these C. elegans proteins (AAT-1 and -3) have been shown to function as catalytic subunits (light chains) of heteromeric amino acid transporters. These proteins need to associate with a glycoprotein heavy chain subunit (ATG-2) to reach the cell surface in a similar manner to their mammalian homologues. AAT-1 and 3 contain a cysteine residue in the second putative extracellular loop through which a disulfide bridge can form with a heavy chain. In contrast six C. elegans members of this family (AAT-4 to -9) lack such a cysteine residue. We show here that one of these transporter proteins, AAT-9, reaches the cell surface in Xenopus oocytes without an exogenous heavy chain and that it functions as an exchanger of aromatic amino acids. Two-electrode voltage clamp experiments demonstrate that AAT-9 displays a substrate-activated conductance. Immunofluorescence shows that it is expressed close to the pharyngeal bulbs within C. elegans neurons. The selective expression of an aat-9 promoter-GFP construct in several neurons of this region and in wall muscle cells around the mouth supports and extends these localization data. Taken together, the results show that AAT-9 is expressed in excitable cells of the nematode head and pharynx in which it may provide a pathway for aromatic amino acid transport.

Gharat V et al. (2024) eNeuro "Role of GLR-1 in age-dependent short-term memory decline."

Gharat V, Papassotiropoulos A, Peter F, de Quervain DJ, Stetak A

[

eNeuro,

2024]

As the global elderly population grows, age-related cognitive decline is becoming an increasingly significant healthcare issue, often leading to various neuropsychiatric disorders. Among the many molecular players involved in memory, AMPA-type glutamate receptors are known to regulate learning and memory, but how their dynamics change with age and affect memory decline is not well understood. Here, we examined the in vivo properties of the AMPA type glutamate receptor GLR-1 in the AVA interneuron of the C. elegans nervous system during physiological aging. We found that both total and membrane-bound GLR-1 receptor levels decrease with age in wild-type worms, regardless of their location along the axon. Using fluorescence recovery after photobleaching (FRAP), we also demonstrated that a reduction in GLR-1 abundance correlates with decreased local, synaptic GLR-1 receptor dynamics. Importantly, we found that reduced GLR-1 levels strongly correlate with the age-related decline in short-term associative memory. Genetic manipulation of GLR-1 stability, either by deleting msi-1 or expressing a ubiquitination-defective GLR-1 (4KR) variant, prevented this age-related reduction in receptor abundance and improved short-term memory performance in older animals, which reached performance levels similar to those of young animals. Overall, our data indicate that AMPA-type glutamate receptor abundance and dynamics are key factors in maintaining memory function, and that changes in these parameters are linked to age-dependent short-term memory decline.Significance statement AMPA-type glutamate receptors are pivotal in synaptic transmission and plasticity, and their dysregulation is linked to neurological conditions and age-related cognitive decline. Despite their importance, the mechanisms regulating these receptors are not fully understood. In this study, we examined age-related changes in the AMPA-type glutamate receptor GLR-1 in Caenorhabditis elegans and assessed its impact on short-term memory decline. Our data show a significant reduction in both the abundance and local turnover of total and membrane-bound GLR-1 receptors as animals age. This decline closely correlates with decreased performance in aversive olfactory memory tasks in older animals. Importantly, inhibiting GLR-1 degradation effectively mitigates short-term memory decline in aged animals.

Hargitai B et al. (2009) Development "xol-1, the master sex-switch gene in C. elegans, is a transcriptional target of the terminal sex-determining factor TRA-1."

Hargitai B, Csankovszki G, Takacs-Vellai K, Blauwkamp TA, Stetak A, Vellai T, Kutnyanszky V

[

Development,

2009]

In the nematode Caenorhabditis elegans, sex is determined by the ratio of X chromosomes to sets of autosomes: XX animals (2X:2A=1.0) develop as hermaphrodites and XO animals (1X:2A=0.5) develop as males. TRA-1, the worm ortholog of Drosophila Cubitus interruptus and mammalian Gli (Glioma-associated homolog) proteins, is the terminal transcription factor of the C. elegans sex-determination pathway, which specifies hermaphrodite fate by repressing male-specific genes. Here we identify a consensus TRA-1 binding site in the regulatory region of xol-1, the master switch gene controlling sex determination and dosage compensation. xol-1 is normally expressed in males, where it promotes male development and prevents dosage compensation. We show that TRA-1 binds to the consensus site in the xol-1 promoter in vitro and inhibits the expression of xol-1 in XX animals in vivo. Furthermore, inactivation of tra-1 enhances, whereas hyperactivation of tra-1 suppresses, lethality in animals with elevated xol-1 activity. These data imply the existence of a regulatory feedback loop within the C. elegans sex-determination and dosage-compensation cascade that ensures the accurate dose of X-linked genes in cells destined to adopt hermaphrodite fate.

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