Biology subjects

Tran, M. A.

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

7 recordsLinked to original sources

bioRxiv2026

The role of Fragile X in the control of vertebrate spinal cord networks

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the leading monogenic cause of autism, resulting from mutations in the Fmr1 gene. While extensive research points to widespread circuit hyperexcitability across cortical and subcortical circuits, the contribution of the spinal cord circuits in the motor phenotypes associated with FXS remains largely unexplored. Given that Fmr1 is expressed in both dorsal and ventral spinal cord, including motoneurons, the possibility exists that loss of its protein product, FMRP, disrupts locomotor circuitry. Here, we investigate whether Fmr1 deletion alters the function of the spinal central pattern generator (CPG) networks and gait-related motor output. Using isolated neonatal spinal cord preparations from Fmr1 knockout (Fmr1 KO) mice, we assessed the ability of spinal circuits to generate coordinated fictive locomotor activity in vitro. In parallel, we quantified the gait parameters and motor performance in freely moving adult mice during unskilled and skill-demanding tasks. Our findings indicate that, despite the absence of FMRP in spinal neurons, neonatal Fmr1 KO spinal cords generated robust and coordinated locomotor rhythms compared to controls. Consistently, adult Fmr1 KO mice exhibited normal gait metrics under baseline conditions. However, these mice displayed hyperactivity and performance deficits during more challenging motor tasks demanding higher coordination. These findings suggest that the fundamental locomotor circuitry is preserved in FXS, likely through compensatory mechanisms. Consequently, motor impairments in FXS may arise primarily from supraspinal or integrative circuit dysfunction, rather than intrinsic deficits in spinal CPG function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/704392v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@19a64cborg.highwire.dtl.DTLVardef@14f8ad2org.highwire.dtl.DTLVardef@1230cbforg.highwire.dtl.DTLVardef@19fd51_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINeonatal Fmr1 KO spinal cords generated robust, coordinated locomotor rhythms similar to controls. C_LIO_LIAdult Fmr1 KO mice exhibited normal gait metrics during baseline, unskilled locomotion. C_LIO_LIFmr1 KO mice displayed hyperactivity and performance deficits during skill-demanding motor tasks. C_LIO_LIFXS motor impairments may arise primarily from supraspinal or integrative circuit dysfunction C_LIO_LISpinal cord circuitry appears to compensate for the fundamental loss of Fmr1 function. C_LI

neuroscience↗

bioRxiv2024

Episodic rhythmicity is generated by a distributed neural network in the developing mammalian spinal cord

Spinal circuits produce diverse motor outputs that coordinate the rhythm and pattern of locomotor movements. Despite the episodic nature of these behaviours, the neural mechanisms encoding these episodes are not well understood. This study investigated mechanisms producing episodic rhythms evoked by dopamine in isolated neonatal mouse spinal cords. Dopamine-induced rhythms were primarily synchronous and propagated rostro-caudally across spinal segments, with occasional asynchronous episodes. Electrical stimulation of the L5 dorsal root could entrain episodes across segments, indicating afferent control of the rhythm generator and a distributed rostro-caudal network. Episodic activity was observed in isolated thoracic or sacral segments after full spinal transection or bilateral ventrolateral funiculus (VLF) lesions, suggesting a distributed network coupled via VLF projections. Rhythmicity was recorded from axons projecting through the VLF and dorsal roots, but not from cholinergic recurrent excitation via motoneurons or isolated dorsal inhibitory circuits. The data suggest episodic rhythmicity is generated by a flexibly coupled network of spinal interneurons distributed throughout the spinal cord.

neuroscience↗

bioRxiv2024

Natural Killer Cell Dysfunction In Human Bladder Cancer Is Caused By Tissue-Specific Suppression of SLAMF6 Signaling

NK cells are innate lymphocytes critical for surveillance of viruses and tumors, however the mechanisms underlying NK cell dysfunction in cancer are incompletely understood. We assessed the effector function of NK cells from bladder cancer patients and found severe dysfunction in NK cells derived from tumors versus peripheral blood. While both peripheral and tumor-infiltrating NK cells exhibited conserved patterns of inhibitory receptor over-expression, this did not explain the observed defects in NK surveillance in bladder tumors. Rather, TME-specific TGF-{beta} and metabolic perturbations such as hypoxia directly suppressed NK cell function. Specifically, an oxygen-dependent reduction in signaling through SLAMF6 was mechanistically responsible for poor NK cell function, as tumor-infiltrating NK cells cultured ex vivo under normoxic conditions exhibited complete restoration of function, while deletion of SLAMF6 abrogated NK cell cytolytic function even under normoxic conditions. Collectively, this work highlights the role of tissue-specific factors in dictating NK cell function, and implicates SLAMF6 signaling as a rational target for immuno-modulation to improve NK cell function in bladder cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/591366v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@18ff2faorg.highwire.dtl.DTLVardef@1991cb6org.highwire.dtl.DTLVardef@12c1a94org.highwire.dtl.DTLVardef@84f87b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Restoration of locomotor function following stimulation of the A13 region in Parkinson's mouse models

Parkinsons disease (PD) is characterized by extensive motor and non-motor dysfunction, including gait disturbance, which is difficult to treat effectively. This study explores the therapeutic potential of targeting the A13 region, a heterogeneous region of the medial zona incerta (mZI) containing dopaminergic, GABAergic, and glutamatergic neurons that has shown relative preservation in PD models. The A13 is identified to project to the mesencephalic locomotor region (MLR), with a subpopulation of cells displaying activity correlating to movement speed, suggesting its role in locomotion. We show that photoactivation of this A13 region can alleviate bradykinesia and akinetic features, while increasing turning in a mouse model of PD. These effects combine disease-specific rescue of function with a possible gain of function. We identified areas of preservation and plasticity within the A13 region using whole-brain imaging. Our findings suggest a global remodeling of afferent and efferent projections of the A13 region, highlighting the zona incertas role as a crucial hub for the rapid selection of motor function. The study unveils the significant pro-locomotor effects of the A13 region and suggests its promising potential as a therapeutic target for PD-related gait dysfunction. SIGNIFICANCE STATEMENTThis work examines the function of the A13 region in locomotion, an area with direct connectivity to locomotor regions in the brainstem. A13 stimulation can restore locomotor function and improve bradykinesia in a PD mouse model.

neuroscience↗

bioRxiv2023

Strategic engineering unlocks in vitro type II polyketide biosynthesis

Microbial polyketides represent a structurally diverse class of secondary metabolites with medicinally relevant properties and are synthesized by polyketide synthases (PKS). While Type I PKSs are large biosynthetic machineries composed of a single polypeptide chain, type II PKSs are minimally composed of a ketosynthase-chain length factor (KS-CLF) and a phosphopantetheinylated acyl carrier protein (holo-ACP) expressed separately. Although type II PKSs are found throughout the bacterial kingdom, and despite their importance to strategic bioengineering, type II PKSs have not been well-studied in vitro: In cases where the KS-CLF can be accessed via E. coli heterologous expression, the cognate ACPs are not activatable by the broad specificity Bacillus subtilis surfactin-producing phosphopantetheinyl transferase (PPTase) Sfp and, conversely, in systems where the ACP can be activated by Sfp, the corresponding KS-CLF is typically not readily obtained. Here, we report the high-yield heterologous expression of both cyanobacterial Gloeocapsa sp. PCC 7428 minimal type II PKS (gloPKS) components in E. coli, which allowed us to functionally reconstitute this minimal type II PKS in vitro. Initially, neither the cognate PPTase nor Sfp converted gloACP to its active holo state. However, by examining sequence differences between Sfp-compatible and -incompatible ACPs, we identified two conserved residues in gloACP that, when mutated, enabled high-yield phosphopantetheinylation of gloACP by Sfp. Using analogous mutations, other previously Sfp-incompatible type II PKS ACPs from different bacterial phyla were also rendered activatable by Sfp. This demonstrates the generalizability of our approach and breaks down a longstanding barrier to type II PKS studies and the exploration of complex biosynthetic pathways.

biochemistry↗

bioRxiv2020

Cold-induced hyperphagia requires AgRP-neuron activation in mice

To maintain energy homeostasis during cold exposure, the increased energy demands of thermogenesis must be counterbalanced by increased energy intake. To investigate the neurobiological mechanisms underlying this cold-induced hyperphagia, we asked whether agouti-related peptide (AgRP) neurons are activated when animals are placed in a cold environment and, if so, whether this response is required for the associated hyperphagia. We report that AgRP-neuron activation occurs rapidly upon acute cold exposure, as do increases of both energy expenditure and energy intake, suggesting the mere perception of cold is sufficient to engage each of these responses. We further report that silencing of AgRP neurons selectively blocks the effect of cold exposure to increase food intake. Together, these findings establish a physiologically important role for AgRP neurons in the hyperphagic response to cold exposure.

neuroscience↗

bioRxiv2020

A point mutation in Ttc26 causes lumbar spinal cord fusion and synchronous hind-limb locomotion in hop mice

Identifying the spinal circuits controlling locomotion is critical for unravelling the mechanisms controlling the production of gaits. Development of the circuits governing left-right coordination relies on axon guidance molecules such as ephrins and netrins. To date, no other class of proteins have been shown to play a role during this process. Here we have analyzed hop mice, which walk with a characteristic hopping gait using their hind legs in synchrony. Fictive locomotion experiments suggest that a local defect in the ventral spinal cord contributes to the aberrant locomotor phenotype. Hop mutant spinal cords had severe morphological defects, including the absence of the ventral midline and a poorly defined border between white and grey matter. The hop mice represent the first model where the left and right central pattern generators (CPGs) are fused to form one central CPG, with a synchronous gait as a functional consequence. These defects were exclusively found in the lumbar domain and were associated with abnormal developmental processes, including a misplaced notochord and reduced induction of ventral progenitor domains. While the underlying mutation in hop mice has been suggested to lie within Ttc26, other genes in close vicinity have been associated with gait defects. By replicating the point mutation within Ttc26, employing CRISPR technology, we observed mice with an identical phenotype, thereby verifying the hop mutation. Thus, we show that the assembly of the lumbar CPG network is dependent on a fully functional TTC26 protein.

neuroscience↗