Biology subjects

Humbert, S.

Publications and source records attributed to Humbert, S..

8 recordsLinked to original sources

bioRxiv2026

HUNTINGTON DISEASE ALTERS THE PATTERNING OF NEOCORTICAL AREA IN MICE

BackgroundHuntington disease (HD) is a neurological disorder caused by an aberrant CAG expansion in the HTT gene, producing a mutant protein (mHTT). Although HD is classically characterized by adult-onset cortical and striatal degeneration, accumulating evidence suggests that altered cortical development may also contribute to disease pathogenesis. ObjectiveWe sought to investigate the impact of mHTT on neocortical patterning, which is a largely unexplored aspect of HD. MethodsUsing the HdhQ140 HD knock-in mouse model, we performed immunofluorescence and in situ hybridization to analyze the patterning of the cortex from embryonic day 10 to postnatal day 7. ResultsDuring embryogenesis, HTT expression exhibited a high medial-to-low lateral gradient in the neocortex, like that observed for key transcription factors involved in cortical patterning. Notably, HTT expression was absent from the cortical hem, a critical patterning center. In HD, the protein gradient remained unchanged whereas the expression in medial pallium seemed increased. During the early development of the cerebral hemispheres, the expression of morphogens and signaling pathways, including Shh, Fgf8, and Wnt/BMP genes, were disrupted in organizing centers, leading to altered expression of major neocortical transcription factors. At postnatal stages, the motor and somatosensory cortical areas were misplaced. These developmental alterations were associated with postnatal sensorimotor deficits relevant to HD. ConclusionsOur findings demonstrate that HD-related neurodevelopmental alterations arise as early as embryonic day 10 in mice. This supports previous work suggesting that defects in brain development contribute to HD pathogenesis prior to clinical onset.

pathology↗

bioRxiv2024

Motion vision is tuned to maximize sensorimotor energy transfer in blowfly flight

Insects achieve agile flight using a sensor-rich control architecture whose embodiment eliminates the need for complex computation. For example, their visual systems are tuned to detect the optic flow associated with specific self-motions, but what functional principle does this tuning embed and how does it facilitate motor control? Here we test the hypothesis that evolution co-tunes physics and physiology by aligning an insects sensors to its dynamically-significant modes of self-motion. Specifically, we show that the tuning of the blowfly motion vision system maximizes the flow of signal energy from gust disturbances and control inputs to sensor outputs, jointly optimizing observability and controllability. This evolutionary principle differs from the conventional engineering-design paradigm of optimizing state estimation, with implications for novel robotic systems combining high performance with low power-consumption.

neuroscience↗

bioRxiv2023

Huntingtin bundles and changes the local proteome of actin filaments in neurons

Huntingtin (HTT) is a large protein whose best-known function being the facilitation of intracellular dynamics along the microtubule network by scaffolding molecular motors complexes. Our recent finding that the defective axonal growth in HD was due to altered growth cone architecture led us to ask whether HTT also influences the cytoskeleton itself. In developing neurons, we found that a large proportion of HTT associates with F-actin in growth cones. Using cell free system and purified recombinant proteins, we observed that HTT binds directly filamentous actin (F-actin) and organizes filaments into bundles. Transmission electron microscopy shows that HTT dimers crosslink adjacent filaments 20 nm apart. We also provide evidence that HTT binding on F-actin modulates the association of other proteins to this cytoskeleton. Notably, HTT limits the association of the growth cone protein Drebrin1 with F-actin. HTT depletion leads to abnormal cytoskeletal organization, localization of Drebrin1 in growth cones, and axonal growth. HTT therefore serves a scaffolding function for the cytoskeleton itself, what might be relevant for HD pathophysiology.

cell biology↗

bioRxiv2023

Human fetal virtual histology with X-ray phase contrast imaging

Human fetal analysis is of fundamental importance in understanding normal and pathological development. Congenital malformations and prenatal deaths are commonly linked to alterations of organs formation during embryonic and fetal life. Normal and pathological developments are not completely understood yet, because access to human fetal samples is difficult and exploratory means are scarce. Here we show the first X-ray phase contrast images of post mortem human fetuses performed at the tissue scale. Imaging was performed on both an entire sample and isolated organs at higher resolution. X-ray phase contrast imaging is based on the detection of refraction of a high energy X-ray beam after sample exposure. We were able to produce a tomographic imaging of human fetal tissues at the beginning of their second trimester at resolutions of 23 {micro}m, 6 {micro}m and 3 {micro}m with high contrast on soft tissues. Our results demonstrate how X-ray phase contrast imaging is a promising technique for human development analysis as it gives high-contrast and high-resolution results for soft and hard tissues. We assume this technique to be a reference in the future of human development studies as it is conservative for rare and precious human specimens.

developmental biology↗

bioRxiv2022

Transgene by Germplasm Interactions Can Impact Transgene Evaluation

Transgenes have been successfully commercialized for qualitatively inherited insect and herbicide resistance traits that show similar effects across genetic backgrounds. However, for quantitative traits like yield, genetic background may affect the measured transgene value. In this paper, we evaluated whether different genetic backgrounds impact the estimated value of a transgene for grain yield, ear height, and anthesis-silking interval for maize by developing isogenic pairs of lines with and without a transgene and testing them in hybrid combination with non-transgenic lines from a complementary heterotic group across eleven environments in the USA. Over all hybrid combinations, the transgene increased yield by 0.2 Mg ha-1. Across multiple non-transgenic lines of the opposing heterotic group, the transgene effect within a line pair ranged from an increase of 0.8 Mg ha-1 for the NSS4 and SS7 transgenic lines to a reduction of 0.3 Mg ha-1 for the NSS5 transgenic line when compared to their non-transgenic isoline. Transgenic hybrids were often taller than non-transgenic hybrids (P<0.05). Anthesis to silking interval was reduced by 4{square}C growing degree units overall, but no transgene x genotype interaction was detected among line pairs. Our results show the importance of testing transgene efficacy across a large sample of elite hybrid pairs to assess the genes value. By only testing in a specific hybrid background, as may be done for qualitative traits like insect resistance, transgenes could be erroneously advanced or eliminated.

plant biology↗

bioRxiv2022

Methods for Evaluating Effects of Transgenes for Quantitative Traits

Transgenes that improve quantitative traits have traditionally been evaluated in one or a few genetic backgrounds across multiple environments. However, testing across multiple genetic backgrounds can be equally important to accurately quantify the value of a transgene for breeding objectives. Creating near-isogenic lines across a wide germplasm space is costly and time consuming, which renders it impractical during early stages of testing. In this experiment, we evaluate three approaches to sample the genetic space while concurrently testing across environments. We created both transgenic and non-transgenic doubled haploid lines, F2:3 lines, and bulk F3 families to determine if all methods resulted in similar estimation of transgene value and to identify the number of yield trial plots from each method necessary to obtain a stable estimate of the transgene value. With one exception, the three methods consistently estimated a similar effect of the transgene. We suggest that bulked F3 lines topcrossed to a tester inbred is the most effective method to estimate the value of a transgene across both genetic space and environments.

plant biology↗

bioRxiv2021

Identification of the key role of white matter alteration in the pathogenesis of Huntington's Disease

Pathogenesis of the inherited neurodegenerative disorder Huntingtons Disease (HD) is complex and progressive, with a long presymptomatic phase in which subtle changes occur in the brain of gene carriers up to 15 years before the onset of symptoms. Thus, there is a need of early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. In particular, recent studies have shown that white matter may be affected early in HD. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, Diffusion Tensor Imaging (DTI), Chemical Exchange Saturation Transfer of glutamate (gluCEST) and Magnetization Transfer (MT) imaging, in order to assess white matter integrity over the life of this very progressive mouse model. Our results show early defects of diffusion properties in the anterior part of the corpus callosum, preceding gluCEST defects in the same region (-10.8% at 8 months, -19% at 12 months) that spread to adjacent regions. At 12 months, frontal (-7.3%) and piriform (-16.7%) cortices showed reduced gluCEST, as well as the pallidum (-21.0%). MT imaging showed reduced signal in the septum (-21.7%) at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the pivotal role of white matter, in the pathogenesis of HD and the pertinence of gluCEST and DTI as biomarkers in HD. Highlights- A knock-in mouse model of Huntingtons disease is longitudinally characterized - A multimodal MRI protocol is performed to identify biomarkers of the disease - The white matter plays a pivotal role in the pathogenesis of the disease - The cortico-striatal pathway seems particularly vulnerable in Huntingtons disease

neuroscience↗

bioRxiv2020

Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin

Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntingtons disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablating in vivo HTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.

neuroscience↗