Biology subjects

Montcouquiol, M.

Publications and source records attributed to Montcouquiol, M..

6 recordsLinked to original sources

bioRxiv2026

Dishevelled2 Condensates control Axon Initial Segment (AIS) assembly and function through MTCL1-Dependent microtubule recruitment.

In the epithelium, Planar Cell Polarity (PCP) signaling coordinates cellular organization along the plane of the tissue, perpendicular to the apicobasal axis. In neurons, polarity is instead expressed through the structural and molecular asymmetry that separates the axon from the somatodendritic compartment. Core PCP proteins are essential for neuronal development and function, and have been linked to neurodevelopmental disorders, including autism spectrum disorders and epilepsy. However, their precise roles in the establishment of neuronal polarity remain incompletely understood. Here, we identify Dishevelled2 (Dvl2), a central PCP signaling scaffold, as a novel component of the axon initial segment (AIS), the proximal axonal domain that maintains neuronal polarity and initiates action potentials. We show that Dvl2 defines, both in vivo and in cultured hippocampal neurons, a proximal subdomain positioned upstream of the major AIS marker Ankyrin-G (Ank-G) and is closely associated with microtubule bundles. Dvl2 is already detected during early axon specification, suggesting that it participates in the initial organization of the proximal axon. Functional depletion of Dvl proteins disrupts AIS architecture, reduces the accumulation of Ankyrin-G and other core AIS components, and impairs the organization of AIS microtubule bundles. These structural defects translate into altered neuronal excitability, with a reduced AIS-dependent component of the action potential. Mechanistically, we identify MTCL1 as a microtubule-associated partner that recruits Dvl2 from biomolecular condensate assemblies onto microtubules. This recruitment requires the DIX and PDZ domains of Dvl2. Notably, selective intracellular binders targeting the Dvl2 PDZ domain perturb Dvl2 condensate organization and compromise AIS formation. Together, our data identify Dvl2 as an organizer of the proximal AIS and reveal a Dvl2-MTCL1-dependent mechanism coupling condensate scaffolding, microtubule organization, and neuronal excitability.

neuroscience↗

bioRxiv2024

The correct temporal connectivity of the DG CA3 circuits involved in declarative memory processes depends on Vangl2-dependent planar cell polarity signaling

In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on the proximal dendrites CA3 pyramidal cells (PCs). MfB/TE synapses have distinctive "detonator" properties due to low intitial release probability and large presynaptic facilitation. The molecular mechanisms shaping the morpho-functional properties of MfB/TE synapses are still poorly understood, though alterations in their morphology are associated with Down syndrome, intellectual disabilities, and Alzheimers disease. Here, we identify the core PCP gene Vangl2 as essential to the morphogenesis and function of MfB/TE synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158. Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs ultrastructural and molecular organisation, resulting in defective synaptic transmission and plasticity. In adult, the early loss of Vangl2 results in a number of hippocampus-dependent memory deficits including characteristic flexibility of declarative memory, organisation and retention of working/ everyday-like memory. These deficits also lead to abnormal generalisation of memories to salient cues and diminished ability to form detailed contextual memories. Together, these results establish Vangl2 as a key regulator of DG-CA3 connectivity and functions. HighlightsO_LIVangl2 is a key regulator of MfB/TE synapses morphogenesis and plasticity in CA3 C_LIO_LIVangl2-mediated GPC4-GPR158 interaction maintains MfB-TE pre-synaptic morphology and function C_LIO_LIVangl2 deletion affects declarative memory in adult mice C_LIO_LIVangl2 function is necessary for contextual learning and its loss leads toa maladaptive fear memory for salient cues C_LI

neuroscience↗

bioRxiv2022

LRP2 contributes to planar cell polarity-dependent coordination of motile cilia function

Motile cilia are protruding organelles on specialized epithelia that beat in a synchronous fashion to propel extracellular fluids. Coordination and orientation of cilia beating on individual cells and across tissues is a complex process dependent on planar cell polarity (PCP) signaling. Asymmetric sorting of PCP pathway components, essential to establish planar polarity, involves trafficking along the endocytic path, but the underlying regulatory processes remain incompletely understood. Here, we identified the endocytic receptor LRP2 as regulator of PCP component trafficking in ependyma, a multi-ciliated cell type that is involved in facilitating flow of the cerebrospinal fluid in the brain ventricular system. Lack of receptor expression in gene-targeted mice results in a failure to sort PCP core proteins to the anterior or posterior cell side and, consequently, in the inability to coordinate cilia arrangement and to aligned beating (loss of rotational and translational polarity). LRP2 deficiency coincides with a failure to sort NHERF1, a cytoplasmic LRP2 adaptor to the anterior cell side. As NHERF1 is essential to translocate PCP core protein Vangl2 to the plasma membrane, these data suggest a molecular mechanism whereby LRP2 interacts with PCP components through NHERF1 to control their asymmetric sorting along the endocytic path. Taken together, our findings identified the endocytic receptor LRP2 as a novel regulator of endosomal trafficking of PCP proteins, ensuring their asymmetric partition and establishment of translational and rotational planar cell polarity in the ependyma.

cell biology↗

bioRxiv2021

Vangl2, a core component of the WNT/PCP pathway, regulates adult hippocampal neurogenesis and age-related decline in cognitive flexibility

Decline in episodic memory is one of the hallmarks of aging and represents one of the most important health problems facing western societies. A key structure in episodic memory is the hippocampal formation and the dentate gyrus in particular, as the continuous production of new dentate granule neurons in this brain region was found to play a crucial role in memory and in age-related decline in memory. As such, understanding the molecular processes that regulate the relationship between adult neurogenesis and aging of memory function holds great therapeutic potential. Recently, we found that Vang-gogh like 2 (Vangl2), a core component of the planar cell polarity signaling pathway, is enriched in the dentate gyrus of adult mice. In this context, we sought to evaluate the involvement of this effector of the Wnt/PCP pathway in both adult neurogenesis and memory abilities in adult and middle-aged mice. Using a heterozygous mouse model carrying a dominant negative mutation in Vangl2 gene, we show that alteration in Vangl2 expression decreases the survival of adult-born granule cells and advances the onset of decrease in cognitive flexibility. Inability of mutant mice to erase old irrelevant information to the benefit of new relevant ones highlights a key role of Vangl2 in interference-based forgetting. Taken together, our findings show for the first that Vangl2 activity may constitute an interesting target to prevent age-related decline in hippocampal plasticity and memory.

neuroscience↗

bioRxiv2020

Scribble controls social behaviors through the regulation of the ERK/Mnk1 pathway

Social behavior is a basic domain affected in several neurodevelopmental disorders. Indeed, deficits in social interest, interactions and recognition represent core symptoms of Autism Spectrum Disorder but are also found associated with a heterogeneous set of neuropsychiatric and rare disorders. The SCRIB gene that codes for the polarity protein SCRIBBLE has been identified as a risk gene for spina bifida, the most common type of open neural tube defect, found at high frequencies in autistic patients, as other congenital anomalies, while the deletions/mutations of the 8q24.3 region encompassing SCRIB genes is associated with multisyndromic and rare disorders. Nonetheless, the potential link between SCRIB and ASD-relevant social phenotypes has not been investigated yet. Hence, we performed an extensive behavioral characterization of the circletail line that carries a mutated version of Scrib. Scribcrc/+ mice displayed reduced social interest, lack of preference for social novelty and social reward, and reduced social habituation while other behavioral domains were unaltered. Social deficits were associated with reduced hippocampal volume, upregulation of ERK phosphorylation in specific hippocampal regions, together with increased c-Fos activity in the same brain areas. Importantly, the social alterations were rescued by both direct and indirect pERK inhibition. These results support a specific link between polarity genes, social behaviors and hippocampal functionality, thus suggesting a role for SCRIB in the etiopathology of neurodevelopmental disorders. Furthermore, our data demonstrate the crucial role of the MAPK/ERK signaling pathway, in underlying the social deficits induced by SCRIB mutation, thus supporting its relevance as a therapeutic target.

neuroscience↗

bioRxiv2019

Selective neurodevelopmental and behavioral deficits in Scrib conditional knock-out mice recapitulate some phenotypes associated with the Verheij/8q23.4 deletion syndrome.

Neurodevelopmental disorders arise from combined defects in processes including cell proliferation, differentiation, migration and commissure formation. The evolutionarily conserved tumor-suppressor protein Scribble (Scrib) serves as a nexus to transduce signals for the establishment of apicobasal and planar cell polarity during these processes. Human SCRIB gene mutations are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij syndrome. In this study, we generated brain-specific conditional cKO mouse mutants and assessed the impact of the Scrib deletion on brain morphogenesis and behavior. We showed that embryonic deletion of Scrib in the telencephalon leads to cortical thickness reduction (microcephaly) and alteration of interhemispheric connectivity (corpus callosum and hippocampal commissure agenesis). We correlated these phenotypes with the identification of novel roles for Scrib, both cell- and non-cell-autonomous, on neuronal migration and axonal guidance respectively. Finally, we show that Scrib cKO mice have psychomotor deficits such as locomotor activity impairment and memory alterations. Altogether, we show that Scrib is essential for early brain development and that the outcomes of its brain-specific disruption support a direct or indirect participation of Scrib to neurodevelopmental pathologies.

neuroscience↗