Biology subjects

Dalva, M. B.

Publications and source records attributed to Dalva, M. B..

5 recordsLinked to original sources

bioRxiv2025

Specific neuroblast-derived signals control both cell migration and fate in the rostral migratory stream

Functional neuronal circuits require neuroblasts migrate to appropriate locations and then differentiate into neuronal subtypes. However, it remains unknown how neuroblasts in the subventricular zone (SVZ) are guided through the rostral migratory stream (RMS) to the olfactory bulb (OB). Here we define EphB2 as a neuroblast-derived cue that controls migration along the RMS and helps to determine cell fate. Within the RMS, EphB2 is expressed selectively in, kinase-active in, and required for the migration of neuroblasts. As neuroblasts enter the OB and differentiate, EphB kinase activity is down-regulated, and in the granule cell layer (GCL), EphB2 expression is down-regulated. Blocking EphB kinase activity or knocking down EphB2 results in defects in migration and premature cellular differentiation in the RMS. Unexpectedly, premature loss of EphB2 expression causes neuroblasts to stop migrating and differentiate into astrocyte-like cells. Thus, EphB2 kinase activity and expression are linked to migration and specification of neuroblast fate.

neuroscience↗

bioRxiv2025

Nano-organization of synapses defines synaptic release properties at cortical neuron dendritic spines

Visualization of the submicron organization of excitatory synapses has revealed an unexpectedly ordered architecture consisting of nanocolumns of synaptic proteins that group into nanomodules which scale in number as spine size increases. How these features are related to synaptic function has remained unclear. Here, using super-resolution followed by live-cell line-scan imaging, we find that the size of the smallest miniature calcium and glutamate events are the same, regardless of whether spines have one or two nanopuncta of PSD-95, and that miniature synaptic response in all spines are best fit by a three term Poisson. Two nanomodule spines exhibit more large events without a significant change in event frequency, with the number of the largest events increasing disproportionately. These data support a model where nanomodules define sites of synaptic release and where the nanoarchitecture of synaptic proteins specifies subtypes of excitatory synapses, with increasing numbers of nanomodules increasing coordinated multivesicular release.

neuroscience↗

bioRxiv2024

VLK drives extracellular phosphorylation of EphB2 to govern the EphB2-NMDAR interaction and injury-induced pain

Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, we find that the presynaptic release of the tyrosine directed-ectokinase, Vertebrate Lonesome Kinase (VLK/Pkdcc), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses, for phosphorylation of the ectodomain of EphB2, and for injury-induced pain. Pkdcc is an essential gene in the nervous system, and VLK is found in synaptic vesicles, and is released from neurons in a SNARE-dependent fashion. VLK is expressed by nociceptive sensory neurons where presynaptic sensory neuron-specific knockout renders mice impervious to post-surgical pain, without changing proprioception. VLK defines an extracellular mechanism that regulates protein-protein interaction and non-opioid-dependent pain in response to injury. One-Sentence SummarySynaptic protein-protein interactions and pain are regulated by the presynaptic release of the extracellular kinase VLK in the spinal cord.

neuroscience↗

bioRxiv2024

Ephrin-B2 promotes nociceptive plasticity and hyperalgesic priming through EphB2-MNK-eIF4E signaling in both mice and humans

Ephrin-B-EphB signaling promotes pain through signaling between dorsal root ganglion (DRG) neurons and spinal cord neurons in the dorsal horn, and through signaling between peripheral cells and EphB receptors expressed by DRG neurons. Previous findings link ephrin-B expression in painful peripheral tissues in patients to chronic pain, suggesting the clinical significance of this signaling, but the direct effects of ephrins on DRG neurons have not been widely studied. We hypothesized that ephrin-B2 would promote nociceptor plasticity and hyperalgesic priming through MNK-eIF4E signaling, a critical mechanism for nociceptive plasticity induced by growth factors, cytokines and nerve injury. Our work demonstrates that ephrin-B2-EphB2 signaling drives activation of MNK-eIF4E in DRG neurons to cause an enhanced response to inflammatory mediator signaling in both mice and humans and hyperalgesic priming in two models in mice. Both male and female mice developed dose-dependent mechanical hypersensitivity in response to ephrin-B2, and both sexes showed hyperalgesic priming when challenged with PGE2 injection into the same hindpaw. Acute nociceptive behaviors and hyperalgesic priming were blocked in mice lacking MNK1 (Mknk1 knockout mice) and by the MNK inhibitor eFT508. Similar effects on hyperalgesic priming were seen in a dural injection model. We generated a sensory neuron specific knockout of EphB2 using Pirt-Cre mice and found that these mice lacked responses to ephrin-B2 injection. We used Ca2+-imaging to determine direct effects of ephrin-B2 on DRG neurons and found that ephrin-B2 treatment enhanced Ca2+ transients in response to PGE2 which were absent in DRG neurons from MNK1-/- and EphB2-PirtCre mice. In experiments on human DRG neurons we found that ephrin-B2 increased eIF4E phosphorylation and enhanced Ca2+ responses to PGE2 treatment, both of which were blocked by eFT508 treatment. We conclude that ephrin-B2 acts directly on mouse and human sensory neurons to induce nociceptor plasticity via MNK-eIF4E signaling. The findings offer insight into how ephrin-B signaling promotes pain, and suggests treatment avenues for prevention or reversal of chronic pain associated with EphB activation in sensory neurons. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/581414v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@9ff5c9org.highwire.dtl.DTLVardef@1c17916org.highwire.dtl.DTLVardef@f4a5b0org.highwire.dtl.DTLVardef@1aa00c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

EphrinB2 knockdown in spinal cord astrocytes preserves diaphragm innervation in a mutant SOD1 mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.

neuroscience↗