Daniel Matus

All Publications

• The N terminus-only (trans) function of the Adhesion GPCR Latrophilin-1 controls multiple processes in reproduction of C. elegans. G3 (Bethesda, Md.) Matúš, D., Post, W. B., Groß, V. E., Knierim, A. B., Kuhn, C. K., Fiedler, F., Tietgen, D. B., Schön, J. L., Schöneberg, T., Prömel, S. 2024

  Abstract

  Adhesion G protein-coupled receptors (aGPCR) are unique molecules. They are able to transmit classical signals via G-protein activation as well as mediate functions solely through their extracellular N termini, completely independently of the seven transmembrane helices domain (7TM) and the C terminus. This dual mode of action is highly unusual for GPCRs and allows for a plethora of possible cellular consequences. However, the physiological implications and molecular details of this N terminus-mediated signaling are poorly understood. Here, we show that several distinct 7TM-independent/trans functions of the aGPCR Latrophilin homolog LAT-1 in the nematode Caenorhabditis elegans together regulate reproduction: sperm guidance, ovulation, and germ cell apoptosis. In these contexts, the receptor elicits its functions in a non-cell autonomous manner. The functions might be realized through alternative splicing of the receptor specifically generating N terminus-only variants. Thus, our findings shed light on the versatility of 7TM-independent/N terminus-only/trans functions of aGPCR and discuss possible molecular details.

  View details for DOI 10.1093/g3journal/jkae206

  View details for PubMedID 39243387

• Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience Matúš, D., Lopez, J. M., Sando, R. C., Südhof, T. C. 2024

  Abstract

  Latrophilin-1 (Lphn1, a.k.a. CIRL1 and CL1; gene symbol Adgrl1) is an Adhesion GPCR that has been implicated in excitatory synaptic transmission as a candidate receptor for α-latrotoxin. Here we analyzed conditional knockin/knockout mice for Lphn1 that contain an extracellular myc-epitope tag. Mice of both sexes were used in all experiments. Surprisingly, we found that Lphn1 is localized in cultured neurons to synaptic nanoclusters that are present in both excitatory and inhibitory synapses. Conditional deletion of Lphn1 in cultured neurons failed to elicit a detectable impairment in excitatory synapses but produced a decrease in inhibitory synapse numbers and synaptic transmission that was most pronounced for synapses close to the neuronal soma. No changes in axonal or dendritic outgrowth or branching were observed. Our data indicate that Lphn1 is among the few postsynaptic adhesion molecules that are present in both excitatory and inhibitory synapses and that Lphn1 by itself is not essential for excitatory synaptic transmission but contributes to inhibitory synaptic connections.Significance Statement Previously, the Adhesion-GPCRs Latrophilin-2/Latrophilin-3 have been shown to mediate excitatory, but not inhibitory, synapse assembly onto discreet dendritic compartments of hippocampal pyramidal neurons. Here we now show that Latrophilin-1 is targeted to both excitatory and inhibitory hippocampal synapses. Unexpectedly, we find that Latrophilin-1 is selectively essential for directing inhibitory synaptic connections to the neuronal soma. Our work supports a model by which Latrophilins are widely used as organizers of synaptic connectivity that act on a subcellular level. In the light of recent findings connecting haploinsufficiency of Latrophilin-1 to a plethora of neurodevelopmental and neuropsychiatric disorders, our study contributes to our understanding of the molecular mechanisms of Latrophilins that need to be targeted in order to address various pathologies.

  View details for DOI 10.1523/JNEUROSCI.1978-23.2024

  View details for PubMedID 38684366

• The Adhesion GPCR and PCP component Flamingo (FMI-1) alters body size and regulates the composition of the extracellular matrix. Matrix biology : journal of the International Society for Matrix Biology Schön, J. L., Groß, V. E., Post, W. B., Daum, A., Matúš, D., Pilz, J., Schnorr, R., Horn, S., Bäumers, M., Weidtkamp-Peters, S., Hughes, S., Schöneberg, T., Prömel, S. 2024

  Abstract

  The extracellular matrix (ECM) is a network of macromolecules that presents a vital scaffold for cells and enables multiple ways of cellular communication. Thus, it is essential for many physiological processes such as development, tissue morphogenesis, homeostasis, the shape and partially the size of the body and its organs. To ensure these, the composition of the ECM is tissue-specific and highly dynamic. ECM homeostasis is therefore tightly controlled by several mechanisms. Here, we show that FMI-1, the homolog of the Adhesion GPCR Flamingo/CELSR/ADGRC in the nematode Caenorhabditis elegans, modulates the composition of the ECM by controlling the production both of ECM molecules such as collagens and also of ECM modifying enzymes. Thereby, FMI-1 affects the morphology and functionality of the nematode´s cuticle, which is mainly composed of ECM, and also modulates the body size. Mechanistic analyses highlight the fact that FMI-1 exerts its function from neurons non-cell autonomously (trans) solely via its extracellular N terminus. Our data support a model, by which the activity of the receptor, which has a well-described role in the planar cell polarity (PCP) pathway, involves the PCP molecule VANG-1, but seems to be independent of the DBL-1/BMP pathway.

  View details for DOI 10.1016/j.matbio.2024.02.005

  View details for PubMedID 38378098

• Latrophilin-1 drives neuron morphogenesis and shapes chemo- and mechanosensation-dependent behavior in C. elegans via a trans function. Biochemical and biophysical research communications Matúš, D., Post, W. B., Horn, S., Schöneberg, T., Prömel, S. 2022; 589: 152-158

  Abstract

  Latrophilins are highly conserved Adhesion GPCRs playing essential roles in the mammalian nervous system and are associated with severe neurological disorders. Recently, it has been shown that murine Latrophilins mediate classical G-protein signals to drive synaptogenesis. However, there is evidence that Latrophilins in the nematode Caenorhabditis elegans can also function independently of their seven-transmembrane domain and C terminus (trans function). Here, we show that Latrophilin-1 acts in trans to mediate morphogenesis of sensory structures in the C. elegans nervous system. This trans function is physiologically relevant in copulation behavior. Detailed expression and RNA-Seq analyses revealed specific LAT-1-positive neurons and first insights into the genetic network that is modulated by the receptor function. We conclude that 7TM-independent functions of Latrophilins are essential for neuronal physiology, possibly complementing canonical functions via G protein-mediated signaling.

  View details for DOI 10.1016/j.bbrc.2021.12.006

  View details for PubMedID 34922196

• G Proteins and GPCRs in C. elegans Development: A Story of Mutual Infidelity. Journal of developmental biology Matúš, D., Prömel, S. 2018; 6 (4)

  Abstract

  Many vital processes during C. elegans development, especially the establishment and maintenance of cell polarity in embryogenesis, are controlled by complex signaling pathways. G protein-coupled receptors (GPCRs), such as the four Frizzled family Wnt receptors, are linchpins in regulating and orchestrating several of these mechanisms. However, despite being GPCRs, which usually couple to G proteins, these receptors do not seem to activate classical heterotrimeric G protein-mediated signaling cascades. The view on signaling during embryogenesis is further complicated by the fact that heterotrimeric G proteins do play essential roles in cell polarity during embryogenesis, but their activity is modulated in a predominantly GPCR-independent manner via G protein regulators such as GEFs GAPs and GDIs. Further, the triggered downstream effectors are not typical. Only very few GPCR-dependent and G protein-mediated signaling pathways have been unambiguously defined in this context. This unusual and highly intriguing concept of separating GPCR function and G-protein activity, which is not restricted to embryogenesis in C. elegans but can also be found in other organisms, allows for essential and multi-faceted ways of regulating cellular communication and response. Although its relevance cannot be debated, its impact is still poorly discussed, and C. elegans is an ideal model to understand the underlying principles.

  View details for DOI 10.3390/jdb6040028

  View details for PubMedID 30477278

  View details for PubMedCentralID PMC6316442