Biology subjects

Bronfman, F. C.

Publications and source records attributed to Bronfman, F. C..

5 recordsLinked to original sources

bioRxiv2025

BDNF-induced axonal mTOR activation promotes Rab5 translation, axonal transport, and CREB phosphorylation in cortical neurons.

Brain-derived neurotrophic factor (BDNF) promotes neuronal plasticity through retrograde signaling from axon terminals to the nucleus, activating CREB-dependent transcription. While this relies on signaling endosomes, the molecular mechanisms enabling their axonal transport remain poorly understood. Using compartmentalized cultures of mouse cortical neurons, we show that axonal BDNF activates mTOR signaling and stimulates local protein synthesis. Translation inhibitors blocked both BDNF-enhanced retrograde transport and nuclear CREB phosphorylation, indicating that axonal protein synthesis is required for long-distance signaling. Among locally synthesized proteins, we identified Rab5, a master regulator of endosomal trafficking. BDNF increased axonal Rab5 levels through TrkB- and mTOR-dependent mechanisms, confirmed by puromycin-PLA for Rab5 and soma-free axon preparations. Axon-specific Rab5 knockdown abolished BDNF-induced retrograde transport and CREB activation, demonstrating that local axonal translation of Rab5 mRNA is essential for neurotrophin signaling propagation. Remarkably, even basal retrograde transport depended on ongoing axonal Rab5 synthesis, revealing a constitutive role for local translation in maintaining axonal trafficking capacity. These findings establish that local axonal translation of trafficking regulators is a prerequisite for axon-to-nucleus neurotrophin signaling, positioning on-demand protein synthesis as a central node in long-distance neuronal communication.

neuroscience↗

bioRxiv2023

Axonal PLC-γ activity is required for BDNF long-distance signaling.

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase receptor B (TrkB) are important signaling proteins that regulate dendritic growth and maintenance in the central nervous system (CNS). After binding of BDNF, TrkB is endocytosed into endosomes and continues signaling within the cell soma, dendrites, and axon. We showed that BDNF signaling initiated in axons triggers long-distance signaling, inducing dendritic arborization in a CREB-dependent manner in cell bodies, processes that depend on axonal dynein and TrkB activities. The binding of BDNF to TrkB triggers the activation of different signaling pathways, including the ERK1/2, PLC-{gamma} and PI3K-mTOR pathways, to induce dendritic growth and synaptic plasticity. How TrkB downstream pathways regulate long-distance signaling is unclear. Here, we studied the role of PLC-{gamma}-Ca2+ in BDNF/TrkB-induced long-distance signaling using compartmentalized microfluidic cultures. We found that dendritic branching and CREB phosphorylation induced by axonal BDNF stimulation require the activation of PLC-{gamma} in the axons of cortical neurons. Locally on axons, BDNF increases PLC-{gamma} phosphorylation and induces intracellular Ca2+ waves in a PLC-{gamma}-dependent manner. Moreover, the transport of BDNF-containing signaling endosomes to the cell body was dependent on PLC-{gamma} activity and intracellular Ca2+ stores. Furthermore, the activity of PLC-{gamma} is required for BDNF-dependent TrkB endocytosis, suggesting a role for the TrkB/PLC-{gamma} signaling pathway in axonal signaling endosome generation.

neuroscience↗

bioRxiv2021

Characterization of an Agarophyton chilense oleoresin containing PPARγ natural ligands with insulin-sensitizing effects in a C57BL/6J mouse model of diet-induced obesity and antioxidant activity in Caenorhabditis elegans.

The biomedical potential of the edible red seaweed Agarophyton chilense (former Gracilaria chilensis) has not been explored. Red seaweeds are enriched in polyunsaturated fatty acids and eicosanoids, which are known natural ligands of the PPAR{gamma} nuclear receptor. PPAR{gamma} is the molecular target of thiazolidinediones (TZDs), drugs used as insulin sensitizers to treat type 2 diabetes mellitus. TZDs medical use is limited due to undesired side effects, the fact that it has triggered the search for partial agonists without the TZDs side effects. We produced A.chilense oleoresin (Gracilex(R)) that induces the activation of PPAR{gamma} without inducing adipocyte differentiation, similar to PPAR{gamma} partial agonists. In a model of high-fat diet-induced obesity in male mice, we showed that treatment with Gracilex(R) improves insulin sensitivity, normalizing altered glucose and insulin parameters. Gracilex(R) was enriched in palmitic acid, arachidonic acid, oleic acid, and lipophilic antioxidants such as {beta}-carotene and tocopherols. Gracilex(R) possesses antioxidant activity in vitro (CUPRAC) and increased the antioxidant capacity in vivo in Caenorhabditis elegans. These findings support the idea that Gracilex(R) is an excellent source of healthy lipids targeting PPAR{gamma} with antioxidant activity and a high nutraceutical value.

physiology↗

bioRxiv2020

BDNF/TrkB signaling endosomes mediate long-distance dendritic growth by activating CREB/PI3K-mTOR-dependent translation in neuronal cell bodies.

Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase receptor B (TrkB) and the p75 neurotrophin receptor (p75) are the primary regulators of dendritic growth in the central nervous system (CNS). After being bound by BDNF, TrkB and p75 are endocytosed into endosomes and continue signaling within the cell soma, dendrites, and axons. We studied the functional role of BDNF axonal signaling in cortical neurons derived from different transgenic mice using compartmentalized cultures in microfluidic devices. We found that axonal BDNF increased dendritic growth from the neuronal cell body in a cAMP response element-binding protein (CREB)-dependent manner. These effects were dependent on axonal TrkB but not p75 activity. Dynein-dependent BDNF-TrkB-containing endosome transport was required for long-distance induction of dendritic growth. Axonal signaling endosomes increased CREB and mTOR kinase activity in the cell body, and this increase in the activity of both proteins was required for general protein translation and the expression of Arc, a plasticity-associated gene, indicating a role for BDNF-TrkB axonal signaling endosomes in coordinating the transcription and translation of genes whose products contribute to learning and memory regulation.

neuroscience↗

bioRxiv2019

The Rab5-Rab11 endosomal pathway is required for BDNF-induced CREB transcriptional regulation in neurons.

Brain-derived neurotrophic factor (BDNF) is a key regulator of the morphology and connectivity of central neurons. We have previously shown that BDNF/TrkB signaling regulates the activity and mobility of the GTPases Rab5 and Rab11, which in turn determine the post-endocytic sorting of signaling TrkB receptors. Moreover, altered Rab5 or Rab11 activity inhibits BDNF-induced dendritic branching. Whether Rab5 or Rab11 activity is important for local events only, or also for regulating nuclear signaling and gene expression, is unknown. Here, we investigated whether BDNF-induced signaling cascades were altered when early and recycling endosomes were disrupted by the expression of dominant negative mutants of Rab5 and Rab11. The activities of both Rab5 and Rab11 were required for sustained activity of Erk1/2 and nuclear CREB phosphorylation and for increased transcription of BDNF-dependent genes containing CRE-binding sites that include activity-regulated genes such as Arc, Dusp1, c-fos and Egr1 and growth and survival genes such as Atf3 and Nf1. Based on our results, we propose that the early and recycling endosomes provide a platform for the integration of neurotrophic signaling from the plasma membrane to the nucleus in neurons and that this mechanism likely regulates neuronal plasticity and neuronal survival. Significance StatementBDNF is a soluble neurotrophic factor that regulates plastic changes in the brain, including dendritic growth, by binding to its plasma membrane receptor TrkB. BDNF/TrkB activates signaling cascades leading to activation of CREB, a key transcription factor regulating circuit development and learning and memory. Our results uncover the cellular mechanisms that central neurons use to integrate the signaling of plasma membrane receptors with nuclear transcriptional responses. We found that the endosomal pathway is required for the signaling cascade initiated by BDNF and its receptors in the plasma membranes to modulate BDNF-dependent gene expression and neuronal dendritic growth mediated by the CREB transcription factor in the nucleus.

cell biology↗