The Temporal Mechanisms Guiding Interneuron Differentiation in the Spinal Cord

Neurogenesis timing is an essential developmental mechanism for neuronal diversity and organization throughout the central nervous system. In the mouse spinal cord, growing evidence is beginning to reveal that neurogenesis timing acts in tandem with spatial molecular controls to diversify molecularly and functionally distinct post-mitotic interneuron subpopulations. Particularly, in some cases, this temporal ordering of interneuron differentiation has been shown to instruct specific sensorimotor circuit wirings. In zebrafish, in vivo preparations have revealed that sequential neurogenesis waves of interneurons and motor neurons form speed-dependent locomotor circuits throughout the spinal cord and brainstem. In the present review, we discuss temporal principals of interneuron diversity taken from both mouse and zebrafish systems highlighting how each can lend illuminating insights to the other. Moving forward, it is important to combine the collective knowledge from different systems to eventually understand how temporally regulated subpopulation function differentially across speed- and/or state-dependent sensorimotor movement tasks.

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Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1515526113 ◽

2016 ◽

Vol 113 (9) ◽

pp. 2514-2519 ◽

Cited By ~ 12

Author(s):

Drew L. Sellers ◽

Jamie M. Bergen ◽

Russell N. Johnson ◽

Heidi Back ◽

John M. Ravits ◽

...

Keyword(s):

Spinal Cord ◽

Motor Neurons ◽

Unmet Need ◽

Nerve Roots ◽

Biologic Drugs ◽

Administration Routes ◽

Macromolecular Drugs ◽

The Central Nervous System ◽

Clinical Potential

A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics.

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Long-term in vivo imaging of mouse spinal cord through an optically cleared intervertebral window

10.1101/2021.09.14.460247 ◽

2021 ◽

Author(s):

Wanjie Wu ◽

Sicong He ◽

Junqiang Wu ◽

Congping Chen ◽

Xuesong Li ◽

...

Keyword(s):

Spinal Cord ◽

Nervous System ◽

Stimulated Raman Scattering ◽

Minimal Invasive ◽

Mouse Spinal Cord ◽

Cord Injury ◽

The Central Nervous System ◽

Communication Pathway

Spinal cord, as part of the central nervous system, accounts for the main communication pathway between the brain and the peripheral nervous system. Spinal cord injury is a devastating and largely irreversible neurological trauma, and can result in lifelong disability and paralysis with no available cure. In vivo spinal cord imaging in mouse models without introducing immunological artifacts is critical to understand spinal cord pathology and discover effective treatments. We developed a minimal-invasive intervertebral window by retaining ligamentum flavum to protect the underlying spinal cord. By introducing an optical clearing method, we achieved repeated two-photon fluorescence and stimulated Raman scattering imaging at subcellular resolution with up to 16 imaging sessions over 167 days and observed no inflammatory response. Using this optically cleared intervertebral window, we studied the neuron-glia dynamics following laser axotomy and observed strengthened contact of microglia with the nodes of Ranvier during axonal degeneration. By enabling long-term, repetitive, stable, high-resolution and inflammation-free imaging of mouse spinal cord, our method provides a reliable platform in the research aiming at understanding and treatment of spinal cord pathology.

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Faculty Opinions recommendation of Transfer of pathogenic and nonpathogenic cytosolic proteins between spinal cord motor neurons in vivo in chimeric mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727458673.793530611 ◽

2017 ◽

Author(s):

Judith S Eisen

Keyword(s):

Spinal Cord ◽

Motor Neurons ◽

Chimeric Mice ◽

Cytosolic Proteins

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Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons

Nature Neuroscience ◽

10.1038/s41593-020-00795-0 ◽

2021 ◽

Vol 24 (4) ◽

pp. 572-583 ◽

Cited By ~ 1

Author(s):

Jacob A. Blum ◽

Sandy Klemm ◽

Jennifer L. Shadrach ◽

Kevin A. Guttenplan ◽

Lisa Nakayama ◽

...

Keyword(s):

Spinal Cord ◽

Single Cell ◽

Motor Neurons ◽

Molecular Diversity ◽

Adult Mouse ◽

Transcriptomic Analysis ◽

Mouse Spinal Cord

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In Vivo Two-Photon Imaging of Neurons and Glia in the Mouse Spinal Cord

Cold Spring Harbor Protocols ◽

10.1101/pdb.prot072264 ◽

2012 ◽

Vol 2012 (12) ◽

pp. pdb.prot072264-pdb.prot072264 ◽

Cited By ~ 5

Author(s):

H. Steffens ◽

F. Nadrigny ◽

F. Kirchhoff

Keyword(s):

Spinal Cord ◽

Mouse Spinal Cord ◽

Two Photon ◽

Photon Imaging ◽

Two Photon Imaging

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Biomaterial Approaches to Modulate Reactive Astroglial Response

Cells Tissues Organs ◽

10.1159/000494667 ◽

2018 ◽

Vol 205 (5-6) ◽

pp. 372-395 ◽

Cited By ~ 10

Author(s):

Jonathan M. Zuidema ◽

Ryan J. Gilbert ◽

Manoj K. Gottipati

Keyword(s):

Spinal Cord ◽

Glial Scar ◽

Secondary Injury ◽

Injury Site ◽

Beneficial Effects ◽

Cord Injury ◽

The Central Nervous System ◽

Preclinical Animal Models

Over several decades, biomaterial scientists have developed materials to spur axonal regeneration and limit secondary injury and tested these materials within preclinical animal models. Rarely, though, are astrocytes examined comprehensively when biomaterials are placed into the injury site. Astrocytes support neuronal function in the central nervous system. Following an injury, astrocytes undergo reactive gliosis and create a glial scar. The astrocytic glial scar forms a dense barrier which restricts the extension of regenerating axons through the injury site. However, there are several beneficial effects of the glial scar, including helping to reform the blood-brain barrier, limiting the extent of secondary injury, and supporting the health of regenerating axons near the injury site. This review provides a brief introduction to the role of astrocytes in the spinal cord, discusses astrocyte phenotypic changes that occur following injury, and highlights studies that explored astrocyte changes in response to biomaterials tested within in vitro or in vivo environments. Overall, we suggest that in order to improve biomaterial designs for spinal cord injury applications, investigators should more thoroughly consider the astrocyte response to such designs.

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