scholarly journals How prolonged expression of Hunchback, a temporal transcription factor, re-wires locomotor circuits

2019 ◽  
Author(s):  
Julia L. Meng ◽  
Zarion D. Marshall ◽  
Meike Lobb-Rabe ◽  
Ellie S. Heckscher
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Synapse Formation ◽  
Target Selection ◽  
Neuromuscular Synapse ◽  
Biomedical Intervention ◽  
Neuronal Stem Cell ◽  
Dendrite Morphogenesis

Abstract:In many CNS regions, neuronal birth timing is associated with circuit membership. In Drosophila larvae, we show U motor neurons are a temporal cohort—a set of non-identical, contiguously-born neurons from a single neuronal stem cell that contribute to the same circuit. We prolong expression of a temporal transcription factor, Hunchback, to increase the number of U motor neurons with early-born molecular identities. On the circuit level, this expands and re-wires the U motor neuron temporal cohort. On the cell biological level, we find novel roles for Hunchback in motor neuron target selection, neuromuscular synapse formation, dendrite morphogenesis, and behavior. These data provide insight into the relationship between stem cell and circuit, show that Hunchback is a potent regulator of circuit assembly, and suggest that temporal transcription factors are molecules that could be altered during evolution or biomedical intervention for the generation of novel circuits.

scholarly journals A novel temporal identity window generates alternating cardinal motor neuron subtypes in a single progenitor lineage

2020 ◽  
Author(s):  
Austin Seroka ◽  
Rita M Yazejian ◽  
Sen-Lin Lai ◽  
Chris Q Doe
Keyword(s):  
Transcription Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Target Selection ◽  
Oblique Muscle ◽  
Spatial Patterning ◽  
Temporal Patterning ◽  
Neuron Morphology ◽  
Temporal Identity ◽  
Necessary And Sufficient

AbstractSpatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. These mechanisms generate cardinal classes of motor neurons (sharing a transcription factor identity and common muscle group targets). In Drosophila, two cardinal classes are Even-skipped (Eve)+ motor neurons projecting to dorsal muscles and Nkx6+ motor neurons projecting to ventral muscles. The Drosophila neuroblast 7-1 (NB7-1) lineage generates distinct Eve+ motor neurons via the temporal transcription factor (TTF) cascade Hunchback (Hb)-Krüppel (Kr)-Pdm-Castor (Cas). Here we show that a newly discovered Kr/Pdm temporal identity window gives rise to an Nkx6+ Eve-motor neuron projecting to ventral oblique muscles, resulting in alternation of cardinal motor neuron subtypes from a single progenitor (Eve>Nkx6>Eve). We show that co-overexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineage and that Kr/Pdm act via Nkx6, which itself is necessary and sufficient for VO motor neuron identity. Lastly, Nkx6 is required for ventral oblique muscle targeting, thereby linking temporal patterning to motor neuron morphology and synaptic target selection. In conclusion, we show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm>Nkx6 pathway is necessary and sufficient to specify VO motor neuron identity and morphology.

scholarly journals A novel temporal identity window generates alternating cardinal motor neuron subtypes in a single progenitor lineage

2020 ◽  
Author(s):  
Austin Q Seroka ◽  
Rita M Yazejian ◽  
Sen-Lin Lai ◽  
Chris Q Doe
Keyword(s):  
Transcription Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Target Selection ◽  
Oblique Muscle ◽  
Birth Date ◽  
Loss Of Function ◽  
Temporal Patterning ◽  
Temporal Identity ◽  
Necessary And Sufficient

Abstract Background: Spatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. These mechanisms generate cardinal classes of motor neurons, sharing a transcription factor identity and common muscle group targets). In Drosophila , two cardinal classes are Even-skipped (Eve)+ motor neurons projecting to dorsal longitudinal muscles and Nkx6+ motor neurons projecting to ventral oblique muscles. The Drosophila neuroblast 7-1 (NB7-1) lineage generates distinct Eve+ motor neurons via the temporal transcription factor (TTF) cascade Hunchback (Hb)-Krüppel (Kr)-Pdm-Castor (Cas). Methods: Here we use sparse labelling and molecular markers to identify a novel VO motor neuron subtype in the NB7-1 lineage, and birth-date this neuron to a Kr+ Pdm+ temporal identity window. We selectively drive overexpression of Kr and Pdm in the NB7-1 lineage, and assay the production and axonal targeting of ectopic VO neurons. We then use gain- and loss-of-function strategies to show that the identity and targeting specificity of the VO neuron is dependent on the transcription factor Nkx6. Results: Here we show that a newly discovered Kr/Pdm temporal identity window gives rise to an Nkx6+ Eve- motor neuron projecting to ventral oblique muscles, resulting in alternation of cardinal motor neuron subtypes from a single progenitor (Eve>Nkx6>Eve). We show that co-overexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineage – the first evidence that this TTF combination specifies neuronal identity. Moreover, we show that the Kr/Pdm combination promotes Nkx6 expression, which itself is necessary and sufficient for ventral oblique muscle targeting, thereby linking temporal patterning to motor neuron synaptic target selection. Conclusions: We show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm>Nkx6 pathway is necessary and sufficient to specify VO motor neuron identity and morphology.

scholarly journals Neuron–glia interactions: the roles of Schwann cells in neuromuscular synapse formation and function

2011 ◽  
Vol 31 (5) ◽  
pp. 295-302 ◽  
Author(s):  
Yoshie Sugiura ◽  
Weichun Lin
Keyword(s):  
Schwann Cells ◽  
Motor Neurons ◽  
Nerve Terminal ◽  
Synapse Formation ◽  
Neuromuscular Synapse ◽  
Synaptic Activity ◽  
Nerve Terminals ◽  
Presynaptic Nerve Terminal ◽  
Presynaptic Nerve Terminals ◽  
And Function

The NMJ (neuromuscular junction) serves as the ultimate output of the motor neurons. The NMJ is composed of a presynaptic nerve terminal, a postsynaptic muscle and perisynaptic glial cells. Emerging evidence has also demonstrated an existence of perisynaptic fibroblast-like cells at the NMJ. In this review, we discuss the importance of Schwann cells, the glial component of the NMJ, in the formation and function of the NMJ. During development, Schwann cells are closely associated with presynaptic nerve terminals and are required for the maintenance of the developing NMJ. After the establishment of the NMJ, Schwann cells actively modulate synaptic activity. Schwann cells also play critical roles in regeneration of the NMJ after nerve injury. Thus, Schwann cells are indispensable for formation and function of the NMJ. Further examination of the interplay among Schwann cells, the nerve and the muscle will provide insights into a better understanding of mechanisms underlying neuromuscular synapse formation and function.

scholarly journals Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Éric Martineau ◽  
Adriana Di Polo ◽  
Christine Vande Velde ◽  
Richard Robitaille
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Axonal Degeneration ◽  
Synapse Formation ◽  
Neuromuscular Junctions ◽  
Motor Units ◽  
Early Event ◽  
Motor Neuron Degeneration ◽  
Single Motor Units

Despite being an early event in ALS, it remains unclear whether the denervation of neuromuscular junctions (NMJ) is simply the first manifestation of a globally degenerating motor neuron. Using in vivo imaging of single axons and their NMJs over a three-month period, we identify that single motor-units are dismantled asynchronously in SOD1G37R mice. We reveal that weeks prior to complete axonal degeneration, the dismantling of axonal branches is accompanied by contemporaneous new axonal sprouting resulting in synapse formation onto nearby NMJs. Denervation events tend to propagate from the first lost NMJ, consistent with a contribution of neuromuscular factors extrinsic to motor neurons, with distal branches being more susceptible. These results show that NMJ denervation in ALS is a complex and dynamic process of continuous denervation and new innervation rather than a manifestation of sudden global motor neuron degeneration.

scholarly journals Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs

2020 ◽  
Author(s):  
Kazunari Onodera ◽  
Daisuke Shimojo ◽  
Yasuharu Ishihara ◽  
Masato Yano ◽  
Fuyuki Miya ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Transcriptome Analysis ◽  
Neuronal Degeneration ◽  
Muscular Atrophy ◽  
Neuromuscular Synapse ◽  
Cag Repeat ◽  
Genome Wide ◽  
Spinal Bulbar Muscular Atrophy ◽  
Disease Specific

Abstract Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients’ pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Here, we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. To investigate motor neuron specific pathology, we purified iPSC-derived motor neurons using flow cytometry and cell sorting based on the motor neuron specific reporter, HB9 e438 ::Venus , and proceeded to the genome-wide transcriptome analysis by RNA sequences. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. Notably, we demonstrated the involvement of the neuromuscular synapse via significant upregulation of Synaptotagmin, R-Spondin2 (RSPO2), and WNT ligands in motor neurons derived from SBMA patients, which are known to be associated with neuromuscular junction (NMJ) formation and acetylcholine receptor (AChR) clustering. These aberrant gene expression in neuromuscular synapses might represent a novel therapeutic target for SBMA.

Regulation of central neuron synaptic targeting by the Drosophila POU protein, Acj6

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2395-2405
Author(s):  
S.J. Certel ◽  
P.J. Clyne ◽  
J.R. Carlson ◽  
W.A. Johnson
Keyword(s):  
Motor Neurons ◽  
Synapse Formation ◽  
Target Selection ◽  
Adult Brain ◽  
Synaptic Targeting ◽  
Amino Terminal ◽  
Pou Domain ◽  
Alternatively Spliced ◽  
The Central Nervous System ◽  
Class Iv

Mutations in the Drosophila class IV POU domain gene, abnormal chemosensory jump 6 (acj6), have previously been shown to cause physiological deficits in odor sensitivity. However, loss of Acj6 function also has a severe detrimental effect upon coordinated larval and adult movement that cannot be explained by the simple loss in odorant detection. In addition to olfactory sensory neurons, Acj6 is expressed in a distinct subset of postmitotic interneurons in the central nervous system from late embryonic to adult stages. In the larval and adult brain, Acj6 is highly expressed in central brain, optic and antennal lobe neurons. Loss of Acj6 function in larval optic lobe neurons results in disorganized retinal axon targeting and synapse selection. Furthermore, the lamina neurons themselves exhibit disorganized synaptic arbors in the medulla of acj6 mutant pupal brains, suggesting that Acj6 may play a role in regulating synaptic connections or structure. To further test this hypothesis, we misexpressed two Acj6 isoforms in motor neurons where they are not normally found. The two Acj6 isoforms are produced from alternatively spliced acj6 transcripts, resulting in significant structural differences in the amino-terminal POU IV box. Acj6 misexpression caused marked alterations at the neuromuscular junction, with contrasting effects upon nerve terminal branching and synapse formation associated with specific Acj6 isoforms. Our results suggest that the class IV POU domain factor, Acj6, may play an important role in regulating synaptic target selection by central neurons and that the amino-terminal POU IV box is important for regulation of Acj6 activity.

scholarly journals Zebrafish Motor Neuron Subtypes Differ Electrically Prior to Axonal Outgrowth

2009 ◽  
Vol 102 (4) ◽  
pp. 2477-2484 ◽  
Author(s):  
Rosa L. Moreno ◽  
Angeles B. Ribera
Keyword(s):  
Spinal Cord ◽  
Transcription Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Expression Patterns ◽  
Membrane Properties ◽  
Spinal Cord Segment ◽  
Factor Expression ◽  
Voltage Dependent ◽  
Transcription Factor Expression

Different muscle targets and transcription factor expression patterns reveal the presence of motor neuron subtypes. However, it is not known whether these subtypes also differ with respect to electrical membrane properties. To address this question, we studied primary motor neurons (PMNs) in the spinal cord of zebrafish embryos. PMN genesis occurs during gastrulation and gives rise to a heterogeneous set of motor neurons that differ with respect to transcription factor expression, muscle targets, and soma location within each spinal cord segment. The unique subtype-specific soma locations and axonal trajectories of two PMNs—MiP (middle) and CaP (caudal)—allowed their identification in situ as early as 17 h postfertilization (hpf), prior to axon genesis. Between 17 and 48 hpf, CaPs and MiPs displayed subtype-specific electrical membrane properties. Voltage-dependent inward and outward currents differed significantly between MiPs and CaPs. Moreover, by 48 hpf, CaPs and MiPs displayed subtype-specific firing behaviors. Our results demonstrate that motor neurons that differ with respect to muscle targets and transcription factor expression acquire subtype-specific electrical membrane properties. Moreover, the differences are evident prior to axon genesis and persist to the latest stage studied, 2 days postfertilization.

scholarly journals Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

2021 ◽  
Vol 14 (6) ◽  
pp. 565
Author(s):  
Yashashree Karpe ◽  
Zhenyu Chen ◽  
Xue-Jun Li
Keyword(s):  
Stem Cell ◽  
Motor Neuron ◽  
Gene Targeting ◽  
Motor Neurons ◽  
Gene Editing ◽  
Critical Role ◽  
Projection Neurons ◽  
Transcription Activator ◽  
Motor Neuron Diseases ◽  
Human Ipscs

Motor neurons are large projection neurons classified into upper and lower motor neurons responsible for controlling the movement of muscles. Degeneration of motor neurons results in progressive muscle weakness, which underlies several debilitating neurological disorders including amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA). With the development of induced pluripotent stem cell (iPSC) technology, human iPSCs can be derived from patients and further differentiated into motor neurons. Motor neuron disease models can also be generated by genetically modifying human pluripotent stem cells. The efficiency of gene targeting in human cells had been very low, but is greatly improved with recent gene editing technologies such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem cell-based models and gene editing tools provides unique paradigms to dissect pathogenic mechanisms and to explore therapeutics for these devastating diseases. Owing to the critical role of several genes in the etiology of motor neuron diseases, targeted gene therapies have been developed, including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing. This review summarizes recent advancements in these areas and discusses future challenges toward the development of transformative medicines for motor neuron diseases.

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