Biology subjects

Ezan, J.

Publications and source records attributed to Ezan, J..

4 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↗

bioRxiv2026

A Female-Specific Microglial Redox Program Gates Susceptibility to Obesity

Chronic consumption of energy-dense, high-fat foods persistently exposes hypothalamic circuits that govern body weight to nutrient excess, progressively altering their activity and thereby promoting obesity. Microglia, the brain resident immune cells, sense circulating lipids, but how their intracellular metabolic programs adapt to chronic dietary excess, and how this contributes to obesity risk, is unclear. Here, we reveal a sex-dependent control of calorie overload by hypothalamic microglial cells. In females, but not males, microglia engage a protective metabolic program with increased antioxidant capacity and mitochondrial network remodeling, conferring resistance to early weight gain. Over time, activation of mTORC1 signaling in microglia disrupts mitochondrial functions and dismantles this transient resilience, culminating in weight gain. These findings identify microglial mTORC1 as a sex-specific switch between resilience and vulnerability to obesity and position microglial metabolism as a tractable target for sex-informed weight control.

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↗