Biology subjects

Higuero, A. M.

Publications and source records attributed to Higuero, A. M..

3 recordsLinked to original sources

bioRxiv2026

Polo-like kinase 1 controls activation of adult neural stem cells and represents a druggable entry-point to boost adult neurogenesis

Neural stem cells (NSCs) persist in the mammalian brain after development, but their potential for replacing neural populations lost in brain damage is dramatically restricted. Quiescence, or the ability to transition in and out of the cell cycle is a hallmark of adult NSCs. It deepens as the organism ages and is regarded as a strategy to protect the reservoirs of NSC for the long term. Deciphering the molecular code of dormancy is a major interest in cellular and molecular biology of ageing and in regenerative medicine since it has important implications for potentially manipulating NSCs to improve tissular homeostasis. In this work we have identified the mitotic kinase Polo like kinase 1 (Plk1) as a novel intrinsic regulator of the dynamic transition between NSC quiescence and activation in adult neurogenic niches. Using quantitative phosphoproteomics to pinpoint mechanistical mediators of the role of Plk1, we have identified the quiescence/activation molecular switch formed by E3 ubiquitin ligase Huwe1 and its target, the transcription factor Ascl1/Mash1, as novel effectors of Plk1 in NSCs. We discover that Plk1 restrains the accumulation of Ascl1/Mash1 by acting upstream of Huwe1, providing a direct molecular connection between completion of the cell cycle and the re-establishment of a low activation state following NSC division, which supports the concept that quiescence is an actively maintained state. Moreover we demonstrate that pharmacological inhibition of Plk1 is sufficient to enhance adult neurogenesis in vivo, identifying Plk1 as a viable target to acutely boost endogenous stem cell activation.

neuroscience↗

bioRxiv2024

Deficient Memory, Long-Term Potentiation and Hippocampal Synaptic Plasticity in Galectin-4-KO Mice.

BACKGROUNDBrain function is influenced by the gut through the microbiota-gut-brain axis. Non-physiological microbiota-depletion or induced gut infection in animal models, have been instrumental to link intestinal alterations to cognitive and mood dysfunctions. However, the effects of specific, controlled, physiologically relevant shifts in commensal microbiota composition on brain function remain poorly understood. METHODSMice deficient in galectin-4 (Lgals4-KO) were used in this study. Gut microbiota was analysed by 16S-rRNA sequencing. Cognitive and mood status were evaluated with specific behavioral tests. Long-term potentiation (LTP) was tested ex vivo and in vivo by electrophysiological methods and in vitro by immunofluorescence and western blot. RNA-sequencing was used for transcriptomic analyses. Golgi-Cox staining and transmission electron microscopy were used for quantitative and morphological assessments of dendritic spines and synapses. RESULTSLgals4-KO mice present an altered intestinal commensal microbiota in the absence of pathogens, deficient memory formation, and impaired hippocampal LTP in vivo and ex vivo. Furthermore, Lgals4-KO neurons show a reduced activation of AMPA receptors and of CaMKII upon chemically induced LTP in vitro. These mice also display significantly lower dendritic spine density and shorter spine length in hippocampal dendrites, as well as an increased area of the postsynaptic densities CONCLUSIONSOur results define a new role for galectin-4 in the modulation of commensal bacteria. We also show that the absence of galectin-4 induces changes in gut microbial composition, along with synaptic alterations and memory impairment, supporting our hypothesis that variations in endogenous microbiota may cause or contribute to relevant neurological pathologies.

neuroscience↗

bioRxiv2017

Neurons define non-myelinated axon segments by the regulation of galectin-4-containingaxon membrane domains

The mechanism underlying selective myelination of axons versus dendrites or neuronal somata relies on the expression of somatodendritic membrane myelination inhibitors (i.e. JAM2). However, axons still present long unmyelinated segments proposed to contribute to axonal plasticity and higher order brain functions. Why these segments remain unmyelinated is still an unresolved issue. The bifunctional lectin galectin-4 (Gal-4) organizes the transport of axon glycoproteins by binding to N-acetyllactosamine (LacNac) termini of N-glycans. We have shown that Gal-4 is sorted to segmental domains (G4Ds) along the axon surface, reminiscent of these long unmyelinated axon segments in cortical neurons. We report here that oligodendrocytes (OLGs) do not deposit myelin on Gal-4 covered surfaces or myelinate axonal G4Ds. In addition, Gal-4 interacts and co-localizes in G4Ds with contactin-1, a marker of non-myelinated nodes of Ranvier. Neither Gal-4 expression nor G4D dimensions are affected by myelin extracts or myelinating OLGs, but are reduced with neuron maturation. As in vitro, Gal-4 is consistently segregated from myelinated structures in the brain. Our data shape the novel concept that neurons establish and regulate axon membrane domains expressing Gal-4, the first inhibitor of myelination identified in axons, whose boundaries delineate myelination-incompetent axon segments along neuron development.

neuroscience↗