Biology subjects

Muller, M. M.

Publications and source records attributed to Muller, M. M..

4 recordsLinked to original sources

bioRxiv2025

MeCP2 binding and genome-lamina reorganization precede long gene activation during mouse corticogenesis

During corticogenesis, neural gene expression is tightly coordinated by chromatin and epigenetic changes, whose misregulation can lead to neurodevelopmental disorders1-4. The role of spatial genome organization--particularly interactions with the nuclear lamina--during these developmental programs remains poorly understood. Here, we combined in utero electroporation with scDam&T-seq to jointly profile genome-lamina contacts and transcriptomes in single cells of the mouse embryonic cortex. Interestingly, we find extensive genome-lamina reorganization during corticogenesis that is strongly biased towards long neuronal genes ([≥]100 kb), which are associated with neurodevelopmental disorders including autism spectrum disorder. Detachment of these genes frequently precedes transcriptional activation, positioning lamina disengagement as an early gene regulatory event. We identify the methyl CpG binding protein 2 (MeCP2)--mutated in Rett syndrome--as a candidate mediator of this process. MeCP2 binds lamina-associated, hydroxymethylated long genes before their repositioning, suggesting that MeCP2 may play a role in genome-lamina reorganization. These findings suggest a link between prevalent genome-lamina reorganization and MeCP2 regulation to ensure proper spatiotemporal activation of long neuronal genes during corticogenesis.

molecular biology↗

bioRxiv2024

Conformational Space of the Translocation Domain of Botulinum Toxin: Atomistic Modeling and Mesoscopic Description of the Coiled-Coil Helix Bundle

The toxicity of botulinum multi-domain neurotoxins (BoNTs) arises from a sequence of molecular events, in which the translocation of the catalytic domain through the membrane of a neurotransmitter vesicle plays a key role. A structural study (Lam et al., Nat. Comm., 2018) of the translocation domain of BoNT suggests that the interaction with the membrane is driven by the transition of an helical switch towards a {beta} hairpin. Atomistic simulations in conjunction with the mesoscopic Twister model are used to investigate the consequences of this proposition for the toxin-membrane interaction. The conformational mobilities of the domain as well as the effect of the membrane, implicitly examined by comparing water and water-ethanol solvents, lead to the conclusion that the transition of the switch modifies the internal dynamics and the effect of membrane hydrophobicity on the whole protein. The central two helices, helix 1 and helix 2, forming two coiled-coil motifs, are analyzed using the Twister model, in which the initial deformation of the membrane by the protein is caused by the presence of local torques arising from asymmetric positions of hydrophobic residues. Different torque distributions are observed depending on the switch conformations and permit to propose an origin for the mechanism opening the membrane.

biophysics↗

bioRxiv2023

Not seeing the forest for the trees: Combination of path integration and landmark cues in human virtual navigation

IntroductionIn order to successfully move from place to place, our brain often combines sensory inputs from various sources by dynamically weighting spatial cues according to their reliability and relevance for a given task. Two of the most important cues in navigation are the spatial arrangement of landmarks in the environment, and the continuous path integration of travelled distances and changes in direction. Several studies have shown that Bayesian integration of cues provides a good explanation for navigation in environments dominated by small numbers of easily identifiable landmarks. However, it remains largely unclear how cues are combined in more complex environments. MethodsTo investigate how humans process and combine landmarks and path integration in complex environments, we conducted a series of triangle completion experiments in virtual reality, in which we varied the number of landmarks from an open steppe to a dense forest, thus going beyond the spatially simple environments that have been studied in the past. We analysed spatial behaviour at both the population and individual level with linear regression models and developed a computational model, based on maximum likelihood estimation (MLE), to infer the underlying combination of cues. ResultsOverall homing performance was optimal in an environment containing three landmarks arranged around the goal location. With more than three landmarks, individual differences between participants in the use of cues are striking. For some, the addition of landmarks does not worsen their performance, whereas for others it seems to impair their use of landmark information. DiscussionIt appears that navigation success in complex environments depends on the ability to identify the correct clearing around the goal location, suggesting that some participants may not be able to see the forest for the trees.

neuroscience↗

bioRxiv2017

Audio-visual synchrony and spatial attention enhance processing of dynamic visual stimulation independently and in parallel: a frequency-tagging study

The neural processing of a visual stimulus can be facilitated by attending to its position or by a co-occurring auditory tone. Using frequency-tagging we investigated whether facilitation by spatial attention and audio-visual synchrony rely on similar neural processes. Participants attended to one of two flickering Gabor patches (14.17 and 17 Hz) located in opposite lower visual fields. Gabor patches further \"pulsed\" (i.e. showed smooth spatial frequency variations) at distinct rates (3.14 and 3.63 Hz). Frequency-modulating an auditory stimulus at the pulse-rate of one of the visual stimuli established audio-visual synchrony. Flicker and pulsed stimulation elicited stimulus-locked rhythmic electrophysiological brain responses that allowed tracking the neural processing of simultaneously presented stimuli. These steady-state responses (SSRs) were quantified in the spectral domain to examine visual stimulus processing under conditions of synchronous vs. asynchronous tone presentation and when respective stimulus positions were attended vs. unattended. Strikingly, unique patterns of effects on pulse- and flicker driven SSRs indicated that spatial attention and audiovisual synchrony facilitated early visual processing in parallel and via different cortical processes. We found attention effects to resemble the classical top-down gain effect facilitating both, flicker and pulse-driven SSRs. Audio-visual synchrony, in turn, only amplified synchrony-producing stimulus aspects (i.e. pulse-driven SSRs) possibly highlighting the role of temporally co-occurring sights and sounds in bottom-up multisensory integration.

neuroscience↗