Biology subjects

Bessereau, J.-L.

Publications and source records attributed to Bessereau, J.-L..

8 recordsLinked to original sources

bioRxiv2026

A nuclear role for the contractile protein troponin I/UNC-27 in regulating muscle aging in C. elegans

Muscle ageing is characterized by evolutionarily conserved subcellular alterations across diverse organisms. In Caenorhabditis elegans, the decline in sarcomeric gene expression is among the earliest detectable ageing-associated changes, emerging at the onset of adulthood. To identify causal regulators of muscle ageing in an unbiased manner, we developed a genetic screening strategy that enables visual monitoring of muscle ageing at both cellular and organismal scales. Using this approach, we identified a mutation that delays the age-associated loss of sarcomeric transcripts. Unexpectedly, the mutation maps to the troponin I gene unc-27, which encodes a conserved regulator of muscle contraction not previously implicated in gene regulation. The mutation alters a single amino acid within a predicted nuclear localization signal (NLS). We found that multiple NLS motifs mediate the active transport of UNC-27 into muscle nuclei from early adulthood onward. Disruption of UNC-27 nuclear localization preserves sarcomeric gene expression during ageing and delays early hallmarks of muscle decline, including proteostatic imbalance and mitochondrial fragmentation. Transcriptomic analyses further revealed that nuclear UNC-27 selectively regulates the expression of genes encoding structural components of the muscle apparatus in adult animals. These results support the existence of a homeostatic sarcomere surveillance pathway, in which a structural protein unexpectedly acquires a transcriptional regulatory role in response to age-associated physiological state. The conservation of NLS motifs in mammalian UNC-27 orthologues suggests that this mechanism may be evolutionarily conserved, with potential relevance to human muscle physiology and disease.

cell biology↗

bioRxiv2025

Axon termination of the SAB motor neurons in C. elegans depends on pre- and postsynaptic activity

Axon termination is a critical step in neural circuit formation, but the contribution of activity from postsynaptic targets to this process remains unclear. Using Caenorhabditis elegans SAB neurons as a model system, we showed that inhibition of muscle activity during a critical period of postembryonic development led to axonal overgrowth and ectopic synapse formation. This effect is mediated by a local retrograde signal and requires neuronal voltage-gated calcium channels (VGCCs) acting cell-autonomously to constrain axon growth. Manipulating SAB neuron excitability demonstrated that increased intrinsic neuronal activity drives overgrowth, while reducing activity suppresses it, establishing a functional link between muscle-derived cues and presynaptic excitability. Transcriptomic analysis and genetic studies further implicate the neuropeptides FLP-18 and NLP-12 as essential modulators of this activity-dependent process. Our findings reveal a temporally and spatially restricted retrograde signaling mechanism in motor neurons, where target activity, neuronal calcium dynamics and neuropeptide signaling cooperate to ensure proper axon termination. These results highlight conserved principles of activity-dependent regulation at neuromuscular junctions and provide a framework for understanding how motor circuits integrate target feedback to sculpt precise connectivity.

neuroscience↗

bioRxiv2025

An extracellular complex between CLE-1/collagen XV/XVIII and Punctin/MADD-4 defines cholinergic synapse identity

The precise localization of postsynaptic receptors opposite neurotransmitter release sites is essential for synaptic function. This alignment relies on adhesion molecules, intracellular scaffolds, and a growing class of extracellular scaffolding proteins. However, how these secreted proteins are retained at synapses remains unclear. We addressed this question using C. elegans neuromuscular junctions, where Punctin, a conserved extracellular synaptic organizer, positions postsynaptic receptors. We identified CLE-1, the ortholog of collagens XV/XVIII, as a key stabilizer of Punctin. Punctin and CLE-1B, the main isoform present at neuromuscular junctions, form a complex and rely on each other for synaptic localization. Punctin undergoes cleavage, and in the absence of CLE-1, specific fragments are lost, resulting in the mislocalization of cholinergic receptors to GABAergic synapses. Additionally, CLE-1 regulates receptor levels independently of Punctin. These findings highlight a crucial extracellular complex that maintains synapse identity.

neuroscience↗

bioRxiv2024

A trans-synaptic IgLON adhesion molecular complex directly contacts and clusters a nicotinic receptor

The localization and clustering of neurotransmitter receptors at appropriate postsynaptic sites is a key step in the control of synaptic transmission. Here, we identify a novel paradigm for the synaptic localization of an ionotropic acetylcholine receptor (AChR) based on the direct interaction of its extracellular domain with a cell adhesion molecule of the IgLON family. Our results show that RIG-5 and ZIG-8, which encode the sole IgLONs in C. elegans, are tethered in the pre- and postsynaptic membranes, respectively, and interact in vivo through their first immunoglobulin-like (Ig) domains. In addition, ZIG-8 traps ACR-16 via a direct cis-interaction between the ZIG-8 Ig2 domain and the base of the large extracellular AChR domain. Such mechanism has never been reported, but all these molecules are conserved during evolution. Similar interactions may directly couple Ig superfamily adhesion molecules and members of the large family of Cys-loop ionotropic receptors, including AChRs, in the mammalian nervous system, and may be relevant in the context of IgLON-associated brain diseases.

neuroscience↗

bioRxiv2024

UNC-30/PITX coordinates neurotransmitter identity with postsynaptic GABA receptor clustering

Terminal selectors are transcription factors that control neuronal identity by regulating the expression of key effector molecules, such as neurotransmitter (NT) biosynthesis proteins, ion channels and neuropeptides. Whether and how terminal selectors control neuronal connectivity is poorly understood. Here, we report that UNC-30 (PITX2/3), the terminal selector of GABA motor neuron identity in C. elegans, is required for NT receptor clustering, a hallmark of postsynaptic differentiation. Animals lacking unc-30 or madd-4B, the short isoform of the MN-secreted synapse organizer madd-4 (Punctin/ADAMTSL), display severe GABA receptor type A (GABAAR) clustering defects in postsynaptic muscle cells. Mechanistically, UNC-30 acts directly to induce and maintain transcription of madd-4B and GABA biosynthesis genes (e.g., unc-25/GAD, unc-47/VGAT). Hence, UNC-30 controls GABAAR clustering on postsynaptic muscle cells and GABA biosynthesis in presynaptic cells, transcriptionally coordinating two critical processes for GABA neurotransmission. Further, we uncover multiple target genes and a dual role for UNC-30 both as an activator and repressor of gene transcription. Our findings on UNC-30 function may contribute to our molecular understanding of human conditions, such as Axenfeld-Rieger syndrome, caused by PITX2 and PITX3 gene mutations.

developmental biology↗

bioRxiv2021

DAF-2/insulin IGF-1 receptor regulates mobility during ageing by integrating opposite inputs from muscle and neuronal tissues

During ageing, preservation of locomotion is generally considered an indicator of sustained good health, in elderlies and in animal models. In C. elegans, mutants of the insulin-IGF-1 receptor DAF-2/IIRc represent a paradigm of healthy ageing, as their increased lifespan is accompanied by a delay in age-related loss of motility. However, these animals are less mobile than wild-type animals in early adulthood. Here we investigated the DAF-2/IIRc- dependent relationship between longevity and motility using an auxin-inducible degron to trigger tissue-specific degradation of endogenous DAF-2/IIRc. As previously reported, inactivation of DAF-2/IIRc in neurons or intestine was sufficient to extend the lifespan of worms, whereas depletion in epidermis, germline or muscle was not. However, neither intestinal nor neuronal depletion of DAF-2/IIRc prevented the age-related loss of motility. In 1-day-old adults, DAF-2/IIRc depletion in neurons reduced motility in a DAF-16/FOXO dependent manner, while muscle depletion had no effect. By contrast, DAF-2 depletion in the muscle of middleage animals improved their motility independently of DAF-16/FOXO but required UNC-120/SRF. Yet, neuronal or muscle DAF-2/IIRc depletion both preserved the mitochondria network in ageing muscle. Overall, these results show that the motility pattern of daf-2 mutants is determined by the sequential and opposing impact of neurons and muscle tissues and can be dissociated from the regulation of the lifespan. This work also provides the characterization of a versatile tool to analyze the tissue-specific contribution of insulin-like signaling in integrated phenotypes at the whole organism level.

physiology↗

bioRxiv2020

The HSPG Syndecan is a core organizer of cholinergic synapses in C. elegans

The extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance and homeostasis. The heparan sulfate proteoglycan syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here we show that SDN-1, the sole ortholog of syndecan in C. elegans, is absolutely required for the synaptic clustering of homomeric 7-like N-acetylcholine receptors (AChR) and regulates the synaptic content of heteromeric L-AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize N-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.

neuroscience↗

bioRxiv2019

SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity

Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here we show that SUSD4, a complement-related transmembrane protein, binds the AMPA receptor subunit GLUA2 and controls its activity-dependent degradation. Several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, are identified as SUSD4 binding partners. SUSD4 is expressed by many neuronal populations starting at the time of synapse formation. Loss-of-function of Susd4 in the mouse prevents long-term depression at cerebellar synapses, and leads to impairment in motor coordination adaptation and learning. Our findings reveal that activity-dependent synaptic plasticity relies on a transmembrane CCP domain-containing protein that regulates the degradation of specific substrates. This mechanism potentially accounts for the role of SUSD4 mutations in neurodevelopmental diseases.

neuroscience↗