Biology subjects

Bruyere, J.

Publications and source records attributed to Bruyere, J..

4 recordsLinked to original sources

bioRxiv2025

A scalable architecture for tuning multistate differentiation ratios in synthetic microbial consortia

Establishing synthetic microbial consortia in competitive environments is often compromised by stochastic colonization bottlenecks, where founder effects lead to the unpredictable dominance of a single strain. Here, we overcome this challenge by engineering a differentiation abacus, a scalable, single-layer recombinase architecture that enables a single progenitor cell to differentiate into up to twelve distinct subpopulations. By arranging competitive excision sites in a linear array, we demonstrate that differentiation ratios can be programmed through rationally tuning recombination-site kinetics and inter-site spacing. This architecture allows the generation of strictly mutually exclusive phenotypes with tunable composition, scaling from simple two-state systems to complex multi-state ensembles without the need for multilayered regulation. Finally, we validate the systems utility in a mouse tumor model, showing that in situ differentiation establishes robust, homogeneous consortia that overcome the colonization variability associated with pre-assembled mixtures. This work provides a versatile and scalable framework for reliably controlling consortia composition for bioproduction, synthetic ecology, and engineered living therapies.

synthetic biology↗

bioRxiv2022

Huntingtin-KIF1A-mediated axonal transport of synaptic vesicle precursors influences synaptic transmission and motor skill learning in mice

Neurotransmitters are released at synapses by synaptic vesicles (SVs), which originate from SV precursors (SVPs) that have traveled along the axon. Because each synapse maintains a pool of SVs, only a small fraction of which are released, it is unclear whether axonal transport of SVPs modifies synaptic function. Here, studying the corticostriatal network both in microfluidic devices and in mice, we find that phosphorylation of the Huntingtin protein (HTT) causes it to recruit the kinesin motor KIF1A, which in turn increases axonal transport of SVPs and synaptic glutamate release. In mice, constitutive HTT phosphorylation leads to SV over-accumulation at synapses, increases the probability of SV release, and impairs motor skill learning on the rotating rod. Silencing KIF1A in these mice restored SV transport and motor skill learning to wild-type levels. Axonal SVP transport within the corticostriatal network thus influences synaptic plasticity and motor skill learning.

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↗

bioRxiv2018

The cortico-striatal circuit regulates sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport

Sensorimotor information processing that underlies normal cognitive and behavioral traits is dysregulated across a subset of neurological and psychiatric disorders. The cross-disease deficit in sensorimotor gating poses a unique opportunity to integrate hierarchical findings at molecular, cellular, through circuitry levels to obtain an in-depth mechanistic understanding of this process that contributes to brain physiology and pathophysiology beyond categorical segmentation of brain disorders. Based on circuitry recording with wild-type mice, we demonstrated that the cortico-striatal projection mediates sensorimotor gating responses during prepulse inhibition (PPI) task. We also found that these circuitry responses were disrupted in Disc1 locus-impairment (LI) mice, a model representing neuropsychiatric conditions. Thus, we hypothesized that Disc1-mediated molecular and cellular machinery along the cortico-striatal circuit may regulate sensorimotor gating. Anatomical and biochemical analyses of Disc1-LI mice revealed attenuated Bdnf transport along the cortico-striatal circuit. Pharmacologically augmenting Bdnf transport by chronic lithium administration, in part via Ser-421 phosphorylation of Huntingtin (Htt) and its integration into the motor machinery, restored the striatal Bdnf levels and PPI deficits in Disc1-LI mice, suggesting that the Bdnf transport attenuation mechanistically underlies the circuitry and behavioral deficits. These results also shed light on a novel mechanism and utility of lithium that is currently used as a major mood stabilizer in clinical settings. Collectively, the present study illustrates integrative biological mechanisms for sensorimotor gating, underscoring the cross-disease nature of this behavioral dimension and translational utility of the findings under the era of precision medicine in brain disorders.

neuroscience↗