scholarly journals Control of spinal motor neuron terminal differentiation through sustained Hoxc8 gene activity

2021 ◽  
Author(s):  
Catarina Catela ◽  
Yifei Weng ◽  
Kailong Wen ◽  
Weidong Feng ◽  
Paschalis Kratsios
Keyword(s):  
Transcription Factors ◽  
Motor Neurons ◽  
Terminal Differentiation ◽  
Differentiation Markers ◽  
Spinal Motor Neuron ◽  
C Elegans ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Evolutionarily Conserved ◽  
Genes Encoding

Spinal motor neurons (MNs) constitute cellular substrates for several movement disorders. Although their early development has received much attention, how spinal MNs become and remain terminally differentiated is poorly understood. Here, we determined the transcriptome of mouse brachial MNs at embryonic and postnatal stages. We found that genes encoding homeodomain (HOX, LIM) transcription factors (TFs), previously implicated in early MN development, continue to be expressed postnatally, suggesting later functions. To test this, we inactivated Hoxc8 at successive stages of MN development. We found that Hoxc8 is not only required to establish but also maintain expression of several MN terminal differentiation markers. Furthermore, we uncovered novel TFs with continuous MN expression, a Hoxc8 dependency for maintained expression of Iroquois (Irx) homeodomain TFs, and a new role for Irx2 in MN development. Our findings dovetail recent observations in C. elegans MNs, pointing toward an evolutionarily conserved role for Hox in neuronal terminal differentiation.

scholarly journals Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias

2021 ◽  
Vol 11 (2) ◽  
pp. 152 ◽  
Author(s):  
Daisy Edmison ◽  
Luyu Wang ◽  
Swetha Gowrishankar
Keyword(s):  
Motor Neurons ◽  
Membrane Trafficking ◽  
Neurological Diseases ◽  
Cellular Component ◽  
Diverse Group ◽  
Microtubule Severing ◽  
Spinal Motor Neurons ◽  
Hereditary Spastic Paraplegias ◽  
Spinal Motor ◽  
Genes Encoding

Hereditary Spastic Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the different classes of HSPs that have been linked to lysosome defects: (1) a subset of complex HSPs where mutations in lysosomal genes are causally linked to the diseases, (2) other complex HSPs where mutation in genes encoding membrane trafficking adaptors lead to lysosomal defects, and (3) a subset of HSPs where mutations affect genes encoding proteins whose function is primarily linked to a different cellular component or organelle such as microtubule severing and Endoplasmic Reticulum-shaping, while also altering to lysosomes. Interestingly, aberrant axonal lysosomes, associated with the latter two subsets of HSPs, are a key feature observed in other neurodegenerative diseases such as Alzheimer’s disease. We discuss how altered lysosome function and trafficking may be a critical contributor to HSP pathology and highlight the need for examining these features in the cortico-spinal motor neurons of HSP mutant models.

scholarly journals unc-3, a gene required for axonal guidance in Caenorhabditis elegans, encodes a member of the O/E family of transcription factors

Development ◽  
1998 ◽  
Vol 125 (8) ◽  
pp. 1561-1568 ◽  
Author(s):  
B.C. Prasad ◽  
B. Ye ◽  
R. Zackhary ◽  
K. Schrader ◽  
G. Seydoux ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Motor Neurons ◽  
Gene Mutations ◽  
Axonal Guidance ◽  
Axonal Outgrowth ◽  
E Proteins ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Dauer Formation ◽  
Neuronal Lineage

The expression of specialized signal transduction components in mammalian olfactory neurons is thought to be regulated by the O/E (Olf-1/EBF) family of transcription factors. The O/E proteins are expressed in cells of the olfactory neuronal lineage throughout development and are also expressed transiently in neurons in the developing nervous system during embryogenesis. We have identified a C. elegans homologue of the mammalian O/E proteins, which displays greater than 80% similarity over 350 amino acids. Like its mammalian homologues, CeO/E is expressed in certain chemosensory neurons (ASI amphid neurons) throughout development and is also expressed transiently in developing motor neurons when these cells undergo axonal outgrowth. We demonstrate that CeO/E is the product of the unc-3 gene, mutations in which cause defects in the axonal outgrowth of motor neurons, as well as defects in dauer formation, a process requiring chemosensory inputs. These observations suggest that the O/E family of transcription factors play a central and evolutionarily conserved role in the expression of proteins essential for axonal pathfinding and/or neuronal differentiation in both sensory and motor neurons.

The zebrafish detour gene is essential for cranial but not spinal motor neuron induction

Development ◽  
1999 ◽  
Vol 126 (12) ◽  
pp. 2727-2737 ◽  
Author(s):  
A. Chandrasekhar ◽  
H.E. Schauerte ◽  
P. Haffter ◽  
J.Y. Kuwada
Keyword(s):  
Spinal Cord ◽  
Cell Death ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Spinal Motor Neuron ◽  
Neuronal Phenotype ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Hh Signaling ◽  
Function Cell

The zebrafish detour (dtr) mutation generates a novel neuronal phenotype. In dtr mutants, most cranial motor neurons, especially the branchiomotor, are missing. However, spinal motor neurons are generated normally. The loss of cranial motor neurons is not due to aberrant hindbrain patterning, failure of neurogenesis, increased cell death or absence of hh expression. Furthermore, activation of the Hh pathway, which normally induces branchiomotor neurons, fails to induce motor neurons in the dtr hindbrain. Despite this, not all Hh-mediated regulation of hindbrain development is abolished since the regulation of a neural gene by Hh is intact in the dtr hindbrain. Finally, dtr can function cell autonomously to induce branchiomotor neurons. These results suggest that detour encodes a component of the Hh signaling pathway that is essential for the induction of motor neurons in the hindbrain but not in the spinal cord and that dtr function is required for the induction of only a subset of Hh-mediated events in the hindbrain.

scholarly journals Single-cell transcriptomic analysis unveils spinal motor neuron subtype diversity underpinning the water-to-land transition in vertebrates

2021 ◽  
Author(s):  
Ee Shan Liau ◽  
Suoqin Jin ◽  
Yen-Chung Chen ◽  
Wei-Szu Liu ◽  
Luok Wen Yong ◽  
...  
Keyword(s):  
Single Cell ◽  
Motor Neurons ◽  
Classification System ◽  
Neural Basis ◽  
Spinal Motor Neuron ◽  
Sensory Stimuli ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Motor Movements ◽  
Unified Classification System

AbstractSpinal motor neurons (MNs) integrate sensory stimuli and brain commands to generate motor movements in vertebrates. Distinct MN populations and their diversity has long been hypothesized to co-evolve with motor circuit to provide the neural basis from undulatory to ambulatory locomotion during aquatic-to-terrestrial transition of vertebrates. However, how these subtypes are evolved remains largely enigmatic. Using single-cell transcriptomics, we investigate heterogeneity in mouse MNs and discover novel segment-specific subtypes. Among limb-innervating MNs, we reveal a diverse neuropeptide code for delineating putative motor pool identities. We further uncovered that axial MNs are subdivided by three conserved and molecularly distinct subpopulations, defined by Satb2, Nr2f2 or Bcl11b expression. Although axial MNs are conserved from cephalochordates to humans, subtype diversity becomes prominent in land animals and appears to continue evolving in humans. Overall, our study provides a unified classification system for spinal MNs and paves the way towards deciphering how neuronal subtypes are evolved.

scholarly journals Optogenetic modulation of TDP-43 oligomerization fast-forwards ALS-related pathologies in the spinal motor neurons

2019 ◽  
Author(s):  
Kazuhide Asakawa ◽  
Hiroshi Handa ◽  
Koichi Kawakami
Keyword(s):  
Motor Neurons ◽  
Light Illumination ◽  
Short Term ◽  
Spinal Motor Neuron ◽  
Spinal Motor Neurons ◽  
Intrinsically Disordered ◽  
Spinal Motor ◽  
Lateral Sclerosis

AbstractCytoplasmic aggregation of TDP-43 characterizes degenerating neurons in most cases of amyotrophic lateral sclerosis (ALS), yet the mechanisms and cellular outcomes of TDP-43 pathology remain largely elusive. Here, we develop an optogenetic TDP-43 variant (opTDP-43), whose multimerization status can be modulated in vivo through external light illumination. Using the translucent zebrafish neuromuscular system, we demonstrate that short-term light stimulation reversibly induces cytoplasmic opTDP-43 mislocalization, but not aggregation, in the spinal motor neuron, leading to an axon outgrowth defect associated with myofiber denervation. In contrast, opTDP-43 forms pathological aggregates in the cytoplasm after longer-term illumination and seeds non-optogenetic TDP-43 aggregation. Furthermore, we find that an ALS-linked mutation in the intrinsically disordered region (IDR) exacerbates the light-dependent opTDP-43 toxicity on locomotor behavior. Together, our results propose that IDR-mediated TDP-43 oligomerization triggers both acute and long-term pathologies of motor neurons, which may be relevant to the pathogenesis and progression of ALS.

scholarly journals Slit/Robo signals prevent spinal motor neuron emigration by organizing the spinal cord basement membrane

2019 ◽  
Author(s):  
Minkyung Kim ◽  
Clare H Lee ◽  
Sarah J Barnum ◽  
Roland CJ Watson ◽  
Jennifer Li ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Basement Membrane ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neural Tube ◽  
Spinal Motor Neuron ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Ventral Neural Tube ◽  
Set Up

AbstractThe developing spinal cord builds a boundary between the CNS and the periphery, in the form of a basement membrane. The spinal cord basement membrane is a barrier that retains CNS neuron cell bodies, while being selectively permeable to specific axon types. Spinal motor neuron cell bodies are located in the ventral neural tube next to the floor plate and project their axons out through the basement membrane to peripheral targets. However, little is known about how spinal motor neuron cell bodies are retained inside the ventral neural tube, while their axons can exit. In previous work, we found that disruption of Slit/Robo signals caused motor neuron emigration outside the spinal cord. In the current study, we investigate how Slit/Robo signals are necessary to keep spinal motor neurons within the neural tube. Our findings show that when Slit/Robo signals were removed from motor neurons, they migrated outside the spinal cord. Furthermore, this emigration was associated with abnormal basement membrane protein expression in the ventral spinal cord. Using Robo2 and Slit2 conditional mutants, we found that motor neuron-derived Slit/Robo signals were required to set up a normal basement membrane in the spinal cord. Together, our results suggest that motor neurons produce Slit signals that are required for the basement membrane assembly to retain motor neuron cell bodies within the spinal cord.

Antibodies Against Cysteine String Proteins Inhibit Evoked Neurotransmitter Release at Xenopus Neuromuscular Junctions

1999 ◽  
Vol 82 (1) ◽  
pp. 50-59 ◽  
Author(s):  
Robert E. Poage ◽  
Stephen D. Meriney ◽  
Cameron B. Gundersen ◽  
Joy A. Umbach
Keyword(s):  
Motor Neurons ◽  
Neurotransmitter Release ◽  
Neuromuscular Junctions ◽  
Selective Inhibition ◽  
Spinal Motor Neurons ◽  
Neurotransmitter Secretion ◽  
Spinal Motor ◽  
Evolutionarily Conserved ◽  
Antibody Effects

Cysteine string proteins (CSPs) are evolutionarily conserved proteins that are associated with synaptic vesicles and other regulated secretory organelles. To investigate the role of CSPs in vertebrate neuromuscular transmission, we introduced anti-CSP antibodies into the cell bodies of Xenopus spinal motor neurons that form synapses with embryonic muscle cells in culture. These antibodies produced a rapid (within 3–6 min), and in most cases complete, inhibition of stimulus-dependent neurotransmitter secretion. However, spontaneous neurotransmitter release was stable (both in frequency and amplitude) throughout the period of antibody exposure. Several control experiments validated the specificity of the anti-CSP antibody effects. First, the anti-CSP antibody actions were not mimicked either by antibodies against another synaptic vesicle protein SV2, or by nonspecific immunoglobins. Second, heat treatment of the anti-CSP antibodies eliminated their effect on evoked secretion. Third, immunoblot experiments showed that the anti-CSP and anti-SV2 antibodies were highly selective for their respective antigens in these Xenopus cultures. We conclude from these results that CSPs are vital constituents of the pathway for regulated neurotransmitter release in vertebrates. Moreover, the selective inhibition of evoked, but not spontaneous transmitter release by anti-CSP antibodies indicates that there is a fundamental difference in the machinery that mediates these secretory processes.

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