Biology subjects

Borodinsky, L. N.

Publications and source records attributed to Borodinsky, L. N..

5 recordsLinked to original sources

bioRxiv2025

Vesicular glutamate release is necessary for neural tube formation

The brain and spinal cord originate from a neural tube that is preceded by a flat structure known as the neural plate during early embryogenesis. In humans, failure of the neural plate to convert into a tube by the fourth week of pregnancy leads to neural tube defects (NTDs), birth defects with serious neurological consequences. The signaling mechanisms governing the process of neural tube morphogenesis are unclear. Here we show that in Xenopus laevis embryos, neural plate cells release glutamate during neural plate folding in a Ca2+ and vesicular glutamate transporter-1 (VGluT1)-dependent manner. Vesicular release of glutamate elicits Ca2+ transients in neural plate cells that correlate with activation of Erk1/2. Knocking down or out VGluT1 leads to NTDs through increased expression of Sox2, neural stem cell transcription factor, and neural plate cell proliferation. Exposure during early pregnancy to neuroactive drugs that disrupt these signaling mechanisms might increase the risk of NTDs in offspring.

neuroscience↗

bioRxiv2023

Non-canonical function of folate/folate receptor 1 during neural tube formation

Folate supplementation reduces the occurrence of neural tube defects, one of the most common and serious birth defects, consisting in the failure of the neural tube to form and close early in pregnancy. The mechanisms underlying neural tube defects and folate action during neural tube formation remain unclear. Here we show that folate receptor 1 (FOLR1) is necessary for the formation of neural tube-like structures in human-cell derived neural organoids. Knockdown of FOLR1 in human neural organoids as well as in the Xenopus laevis in vivo model leads to neural tube defects that are rescued by pteroate, a folate precursor that binds to FOLR1 but is unable to participate in metabolic pathways. We demonstrate that FOLR1 interacts with and opposes the function of CD2-associated protein (CD2AP), a molecule that we find is essential for apical endocytosis and the spatiotemporal turnover of the cell adherens junction component C-cadherin in neural plate cells. The counteracting action of FOLR1 on these processes is mediated by regulating CD2AP protein level via a degradation-dependent mechanism. In addition, folate and pteroate increase Ca2+ transient frequency in the neural plate in a FOLR1-dependent manner, suggesting that folate/FOLR1 signal intracellularly to regulate neural plate folding. This study identifies a mechanism of action of folate distinct from its vitamin function during neural tube formation.

neuroscience↗

bioRxiv2022

Postsynaptic receptors regulate presynaptic neurotransmitter stability

Stable matching of neurotransmitters with their receptors is fundamental to synapse function, to achieve reliable and robust communication in neural circuits. Presynaptic neurotransmitters regulate selection of postsynaptic transmitter receptors. However, whether postsynaptic receptors regulate selection of presynaptic transmitters is unknown. Here we show that blockade of postsynaptic acetylcholine receptors at the neuromuscular junction leads to loss of the cholinergic phenotype in motor neurons and stabilization of an earlier, developmentally transient glutamatergic phenotype. Exogenous postsynaptic expression of GABAA receptors leads to the stabilization of an earlier, developmentally transient GABAergic motor neuron phenotype. Both acetylcholine receptors and GABA receptors are linked to presynaptic neurons through trans-synaptic bridges. Knock-down of different components of these trans-synaptic bridges prevents stabilization of the cholinergic and GABAergic phenotypes. We conclude that this bidirectional communication enforces a match between transmitter and receptor and ensures the fidelity of synaptic transmission. Our findings suggest a role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.

neuroscience↗

bioRxiv2021

Injury-induced Erk1/2 signaling enhances Ca2+ activity and is necessary for regeneration of spinal cord and skeletal muscle

The transition of stem cells from quiescence to proliferation enables tissues to self-repair. The signaling mechanisms driving these stem-cell-status decisions are still unclear. Ca2+ and the extracellular signal-regulated kinase (Erk1/2) are two signaling pathways that have the potential to coordinate multiple signals to promote a specific cellular response. They both play important roles during development but their roles during regeneration are not fully deciphered. Here we show in Xenopus laevis larvae that both Ca2+ and Erk1/2 signaling pathways are activated after tail amputation. In response to injury, we find that Erk1/2 signaling is activated in neural and muscle stem cells and is necessary for spinal cord and skeletal muscle regeneration. Finally, we show in vivo that Erk1/2 action is necessary for an injury-induced increase in intracellular store-dependent Ca2+ dynamics in skeletal muscle-associated tissues but that in spinal cord, injury increases Ca2+ influx-dependent Ca2+ activity independent of Erk1/2 signaling. This study suggests that precise temporal and tissue-specific activation of Ca2+ and Erk1/2 pathways is essential for regulating tissue regeneration.

neuroscience↗

bioRxiv2020

Non-canonical Hedgehog signaling regulates spinal cord and muscle regeneration

Inducing regeneration in injured spinal cord represents one of modern medicine greatest challenges. Research from a variety of model organisms indicates that Hedgehog (Hh) signaling may be a useful target to drive regeneration. However, the mechanisms of Hedgehog signaling-mediated tissue regeneration remain unclear. Here we examined Hh signaling during post-amputation tail regeneration in Xenopus laevis larvae. We found that while Smoothened (Smo) activity is essential for proper spinal cord and skeletal muscle regeneration, transcriptional activity of the canonical Hh effector Gli is repressed immediately following amputation, and inhibition of Gli1/2 expression or transcriptional activity has minimal effects on regeneration. In contrast, we demonstrate that protein kinase A (PKA) is necessary for regeneration of both muscle and spinal cord, in concert with and independent of Smo respectively, and that its downstream effector CREB is activated in spinal cord following amputation. Our findings indicate that non-canonical mechanisms of Hh signaling are necessary for spinal cord and muscle regeneration.

neuroscience↗