Biology subjects

Salzer, J. L.

Publications and source records attributed to Salzer, J. L..

6 recordsLinked to original sources

bioRxiv2026

SnapG: An Automated Tool for Myelin g-ratio Measurement with Batch Processing Capability

The g-ratio, calculated as the axon diameter divided by the total myelinated fiber diameter, is widely used to assess the degree of myelination in the central and peripheral nervous systems. Changes in g-ratios accompany demyelinating, hypomyelinating, and remyelinating conditions, and can also result from activity-dependent, adaptive myelination. Although manual tracing from electron micrographs has been the gold-standard to measure g-ratios, this process is laborious and limits throughput. To address this challenge, we developed SnapG, an automated and user-friendly software tool to streamline g-ratio analysis from electron micrographs. SnapG implements an end-to-end pipeline for axon and myelin segmentation on EM images. The tool integrates robust segmentation and post-processing steps to extract axon and fiber diameters and generates both per-image and cohort-level summary statistics. SnapG produces g-ratio distributions that agree well with expert manual annotations and established tools across imaging modalities. It reduces user intervention, supports large image and batch processing, and achieves faster processing times while delivering accurate, reproducible measurements. SnapGs automated reporting thereby facilitates high-throughput analyses and improves consistency across experiments. SnapG can accelerate studies of myelin biology and provides a practical alternative to existing tools.

neuroscience↗

bioRxiv2023

Multi-parametric MRI can detect enhanced myelination in the Gli1-/- mouse brain

This study investigated the potential of combining multiple MR parameters to enhance the characterization of myelin in the mouse brain. We collected ex vivo multi-parametric MR data at 7 Tesla from control and Gli1-/- mice; the latter exhibit enhanced myelination at postnatal day 10 (P10) in the corpus callosum and cortex. The MR data included relaxivity, magnetization transfer, and diffusion measurements, each targeting distinct myelin properties. This analysis was followed by and compared to myelin basic protein (MBP) staining of the same samples. Although a majority of the MR parameters included in this study showed significant differences in the corpus callosum between the control and Gli1-/- mice, only T2, T1/T2, and radial diffusivity (RD) demonstrated a significant correlation with MBP values. Based on data from the corpus callosum, partial least square regression suggested that combining T2, T1/T2, and inhomogeneous magnetization transfer ratio could explain approximately 80% of the variance in the MBP values. Myelin predictions based on these three parameters yielded stronger correlations with the MBP values in the P10 mouse brain corpus callosum than any single MR parameter. In the motor cortex, combining T2, T1/T2, and radial kurtosis could explain over 90% of the variance in the MBP values at P10. This study demonstrates the utility of multi-parametric MRI in improving the detection of myelin changes in the mouse brain.

bioengineering↗

bioRxiv2021

Gli1 regulates the postnatal acquisition of peripheral nerve architecture

Peripheral nerves are organized into discrete cellular compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium - a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a peripheral neuropathy with similar defects. Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs non-canonically i.e., independent of hedgehog signaling. Gli1 and Dhh also have non-redundant activities. In contrast to Dhh nulls, Gli1 nulls have a normal perineurium. Like Dhh nulls, Gli1 nulls form minifascicles, which we show likely arise from EFs. Thus, Dhh and Gli1 are independent signals: Gli1 is dispensable for perineurial development but functions cooperatively with Dhh to drive normal endoneurial development. During development, Gli1 also regulates endoneurial extracellular matrix production, nerve vascular organization, and has modest, non-autonomous effects on SC sorting and myelination of axons. Finally, in adult nerves, induced deletion of Gli1 is sufficient to drive minifascicle formation. Thus, Gli1 regulates the development and is required to maintain the endoneurial architecture of peripheral nerves. SIGNIFICANCE STATEMENTPeripheral nerves are organized into distinct cellular/ECM compartments: the epineurium, perineurium and endoneurium. This organization, with its associated cellular constituents, are critical for the structural and metabolic support of nerves and their response to injury. Here, we show Gli1 - a transcription factor normally expressed downstream of hedgehog signaling - is required for the proper organization of the endoneurium but not the perineurium. Unexpectedly, Gli1 expression by endoneurial cells is independent of, and functions non-redundantly with, Schwann Cell-derived Desert Hedgehog in regulating peripheral nerve architecture. These results further delineate how peripheral nerves acquire their distinctive organization during normal development and highlight mechanisms that may regulate their reorganization in pathologic settings including peripheral neuropathies and nerve injury.

neuroscience↗

bioRxiv2021

Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain

In the adult mammalian brain, Gli1 expressing neural stem cells reside in the subventricular zone and their progeny are recruited to sites of demyelination in the white matter where they generate new oligodendrocytes, the myelin forming cells. Remarkably, genetic loss or pharmacologic inhibition of Gli1 enhances the efficacy of remyelination by these neural stem cells. To understand the molecular mechanisms involved, we performed a transcriptomic analysis of this Gli1-pool of neural stem cells. We compared murine NSCs with either intact or deficient Gli1 expression from adult mice on a control diet or on a cuprizone diet which induces widespread demyelination. These data will be a valuable resource for identifying therapeutic targets for enhancing remyelination in demyelinating diseases like multiple sclerosis.

neuroscience↗

bioRxiv2019

Gli2 is necessary for migration of ventral Neural Stem Cells to demyelinated lesions

Enhancing repair of myelin is an important therapeutic goal in many neurological disorders characterized by demyelination. In the healthy adult brain, ventral neural stem cells in the sub-ventricular zone are marked by Gli1 expression and do not generate oligodendrocytes. However, in response to demyelination they migrate to lesions and differentiate into oligodendrocytes. Inhibition of Gli1 further increases their contribution to remyelination. Gli1 and Gli2 are both transcriptional effectors of the Sonic Hedgehog pathway with highly conserved domains but the role of Gli2 in remyelination by ventral neural stem cells is not clear. Here we show that while genetic ablation of Gli1 in the ventral neural stem cells increases remyelination, loss of Gli2 in these cells decreases their migration to the white matter lesion and reduces their differentiation into mature oligodendrocytes. These studies indicate Gli1 and Gli2 have distinct, non-redundant functions in NSCs, including that Gli2 is essential for the enhanced remyelination mediated by Gli1 inhibition. They highlight the importance of designing specific Gli1 inhibitors that do not inhibit Gli2 as a strategy for therapies targeting the Shh pathway.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC=\"FIGDIR/small/668418v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@177fa0aorg.highwire.dtl.DTLVardef@1c0a954org.highwire.dtl.DTLVardef@1accdc5org.highwire.dtl.DTLVardef@1f97eeb_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2018

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS). The precise role of microglia during demyelination, and the relative contributions of microglia vs. peripheral macrophages, are incompletely understood. Here, using a genetic fate mapping strategy, we identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Pharmacological depletion of microglia demonstrates these cells are necessary for the demyelination, loss of oligodendrocytes, and reactive astrocytosis normally evident in this model. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these damaged myelin sheaths are lost upon-repopulation of microglia. Injection of colony-stimulating factor-1 to drive focal microgliosis in white matter is sufficient to induce focal demyelination in vivo. These studies indicate activated microglia are required for demyelination that results from primary myelin pathology and are sufficient to induce demyelination directly.

neuroscience↗