scholarly journals Robo1 and 2 repellent receptors cooperate to guide facial neuron cell migration and axon projections in the embryonic mouse hindbrain

2018 ◽  
Author(s):  
Hannah N Gruner ◽  
Minkyung Kim ◽  
Grant S Mastick
Keyword(s):  
Cell Migration ◽  
Facial Nerve ◽  
Motor Neurons ◽  
Time Course ◽  
Floor Plate ◽  
Exit Point ◽  
Embryonic Mouse ◽  
Mutant Mouse Embryos ◽  
Redundant Functions ◽  
Double Mutant Mouse

Background: The facial nerve is necessary for our ability to eat, speak, and make facial expressions. Both the axons and cell bodies of the facial nerve undergo a complex embryonic migration pattern involving migration of the cell bodies caudally and tangentially through rhombomeres, and simultaneously the axons projecting to exit the hindbrain to form the facial nerve. Results: Our goal in this study was to test the functions of the chemorepulsive receptors Robo1 and Robo2 in facial neuron and axon migration by analyzing genetically marked motor neurons in double mutant mouse embryos through the migration time course, E10.0-E13.5. In Robo1/2 double mutants, axon and cell body migration errors were more severe than in single mutants. Most axons did not make it to their motor exit point, and instead projected into and longitudinally within the floor plate. Surprisingly, some facial neurons had bifurcated axons that either exited or projected into the floor plate. At the same time, a subset of mutant facial cell bodies failed to migrate caudally, and instead shifted into the floor plate. Conclusions: Robo1 and Robo2 have redundant functions to guide multiple aspects of the complex cell migration of the facial nucleus, as well as regulating axon trajectories and suppressing formation of ectopic axons.

scholarly journals Motor neuron pathfinding following rhombomere reversals in the chick embryo hindbrain

Development ◽  
1992 ◽  
Vol 114 (3) ◽  
pp. 663-673 ◽  
Author(s):  
S. Guthrie ◽  
A. Lumsden
Keyword(s):  
Chick Embryo ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Initial Phase ◽  
Considerable Increase ◽  
Floor Plate ◽  
Axon Outgrowth ◽  
Exit Point ◽  
Sharp Turn ◽  
Late Stages

Motor neurons are segmentally organised in the developing chick hindbrain, with groups of neurons occupying pairs of hindbrain segments or rhombomeres. The branchiomotor nucleus of the trigeminal nerve occupies rhombomeres 2 and 3 (r2 and r3), that of the facial nerve r4 and r5, and that of the glossopharyngeal nerve r6 and r7. Branchiomotor neuron cell bodies lie within the basal plate, forming columns on either side of the ventral midline floor plate. Axons originating in rhombomeres 2, 4 and 6 grow laterally (dorsally) towards the exit points located in the alar plates of these rhombomeres, while axons originating in odd-numbered rhombomeres 3 and 5 grow laterally and then rostrally, crossing a rhombomere boundary to reach their exit point. Examination of the trajectories of motor axons in odd-numbered segments at late stages of development (19–25) showed stereotyped pathways, in which axons grew laterally before making a sharp turn rostrally. During the initial phase of outgrowth (stage 14–15), however, axons had meandering courses and did not grow in a directed fashion towards their exit point. When r3 or r5 was transplanted with reversed rostrocaudal polarity prior to motor axon outgrowth, the majority of axons grew to their appropriate, rostral exit point, despite the inverted neuroepithelial polarity. In r3 reversals, however, there was a considerable increase in the normally small number of axons that grew out via the caudal, r4 exit point. These findings are discussed with relevance to the factors involved in motor neuron specification and axon outgrowth in the developing hindbrain.

scholarly journals Ras-mediated activation of the TORC2–PKB pathway is critical for chemotaxis

2010 ◽  
Vol 190 (2) ◽  
pp. 233-245 ◽  
Author(s):  
Huaqing Cai ◽  
Satarupa Das ◽  
Yoichiro Kamimura ◽  
Yu Long ◽  
Carole A. Parent ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Polymerization ◽  
Time Course ◽  
Specific Inhibitor ◽  
Ras Proteins ◽  
Extracellular Signaling ◽  
Upstream Regulator ◽  
Pkb Phosphorylation ◽  
G Protein Coupled

In chemotactic cells, G protein–coupled receptors activate Ras proteins, but it is unclear how Ras-associated pathways link extracellular signaling to cell migration. We show that, in Dictyostelium discoideum, activated forms of RasC prolong the time course of TORC2 (target of rapamycin [Tor] complex 2)-mediated activation of a myristoylated protein kinase B (PKB; PKBR1) and the phosphorylation of PKB substrates, independently of phosphatidylinositol-(3,4,5)-trisphosphate. Paralleling these changes, the kinetics of chemoattractant-induced adenylyl cyclase activation and actin polymerization are extended, pseudopodial activity is increased and mislocalized, and chemotaxis is impaired. The effects of activated RasC are suppressed by deletion of the TORC2 subunit PiaA. In vitro RasCQ62L-dependent PKB phosphorylation can be rapidly initiated by the addition of a PiaA-associated immunocomplex to membranes of TORC2-deficient cells and blocked by TOR-specific inhibitor PP242. Furthermore, TORC2 binds specifically to the activated form of RasC. These results demonstrate that RasC is an upstream regulator of TORC2 and that the TORC2–PKB signaling mediates effects of activated Ras proteins on the cytoskeleton and cell migration.

Sonic hedgehog synergizes with the extracellular matrix protein vitronectin to induce spinal motor neuron differentiation

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 333-342 ◽  
Author(s):  
S. Pons ◽  
E. Marti
Keyword(s):  
Extracellular Matrix ◽  
Motor Neuron ◽  
Sonic Hedgehog ◽  
Motor Neurons ◽  
Neural Tube ◽  
Matrix Protein ◽  
Floor Plate ◽  
Binding Domain ◽  
Extracellular Matrix Protein ◽  
Neuron Differentiation

Patterning of the vertebrate neural tube depends on intercellular signals emanating from sources such as the notochord and the floor plate. The secreted protein Sonic hedgehog and the extracellular matrix protein Vitronectin are both expressed in these signalling centres and have both been implicated in the generation of ventral neurons. The proteolytic processing of Sonic hedgehog is fundamental for its signalling properties. This processing generates two secreted peptides with all the inducing activity of Shh residing in the highly conserved 19 kDa amino-terminal peptide (N-Shh). Here we show that Vitronectin is also proteolitically processed in the embryonic chick notochord, floor plate and ventral neural tube and that this processing is spatiotemporally correlated with the generation of motor neurons. The processing of Vitronectin produces two fragments of 54 kDa and 45 kDa, as previously described for Vitronectin isolated from chick yolk. The 45 kDa fragment lacks the heparin-binding domain and the integrin-binding domain, RGD, present in the non-processed Vitronectin glycoprotein. Here we show that N-Shh binds to the three forms of Vitronectin (70, 54 and 45 kDa) isolated from embryonic tissue, although is preferentially associated with the 45 kDa form. Furthermore, in cultures of dissociated neuroepithelial cells, the combined addition of N-Shh and Vitronectin significantly increases the extent of motor neuron differentiation, as compared to the low or absent inducing capabilities of either N-Shh or Vitronectin alone. Thus, we conclude that the differentiation of motor neurons is enhanced by the synergistic action of N-Shh and Vitronectin, and that Vitronectin may be necessary for the proper presentation of the morphogen N-Shh to one of its target cells, the differentiating motor neurons.

scholarly journals Hypoglossal-facial ‘side’-to-side neurorrhaphy combined with electrical myostimulation for facial palsy in rats

2018 ◽  
Vol 9 (1) ◽  
pp. 167-174
Author(s):  
Binbin Wang ◽  
Shiwei Wang ◽  
Song Liu ◽  
Shaodong Zhang ◽  
Dezhi Li ◽  
...  
Keyword(s):  
Facial Nerve ◽  
Motor Neurons ◽  
Functional Recovery ◽  
Rat Model ◽  
Facial Palsy ◽  
Crush Injury ◽  
Nerve Crush ◽  
Retrograde Labeling ◽  
Electrophysiological Examination ◽  
Nerve Crush Injury

Abstract Introduction This study investigated the effect of combining hypoglossal-facial nerve “side”-to-side neurorrhaphy and electrical myostimulation in a rat model of facial palsy. Methods Rats with facial nerve crush injury were subjected to control condition, monotherapy of either neurorrhaphy or electrical myostimulation, or bitherapy of the two treatments. After 1, 3, and 6 months, rats were performed the facial symmetry evaluation, electrophysiological examination and the retrograde labeling of motor neurons. Results As early as 3 months after injury, face symmetry significantly improved in rats of the bitherapy group. At 3 or 6 months after injury, either the parameters of electrophysiological examination or the number of labeled motor neurons were significantly increased in the bitherapy group than in any other group. Discussion The combination of neurorrhaphy and electrical myostimulation effectively promoted the functional recovery after facial nerve crush injury.

scholarly journals Dynamics of neural crest-derived cell migration in the embryonic mouse gut

2004 ◽  
Vol 270 (2) ◽  
pp. 455-473 ◽  
Author(s):  
H.M. Young ◽  
A.J. Bergner ◽  
R.B. Anderson ◽  
H. Enomoto ◽  
J. Milbrandt ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Embryonic Mouse

scholarly journals Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4475-4488 ◽  
Author(s):  
Erik A. Lundquist ◽  
Peter W. Reddien ◽  
Erika Hartwieg ◽  
H. Robert Horvitz ◽  
Cornelia I. Bargmann
Keyword(s):  
Cell Migration ◽  
Axon Guidance ◽  
Apoptotic Cell ◽  
Regulatory Proteins ◽  
Axon Pathfinding ◽  
C Elegans ◽  
Cell Corpse ◽  
And Function ◽  
Redundant Functions ◽  
Caenorhabditis Elegans Genome

The Caenorhabditis elegans genome contains three rac-like genes, ced-10, mig-2, and rac-2. We report that ced-10, mig-2 and rac-2 act redundantly in axon pathfinding: inactivating one gene had little effect, but inactivating two or more genes perturbed both axon outgrowth and guidance. mig-2 and ced-10 also have redundant functions in some cell migrations. By contrast, ced-10 is uniquely required for cell-corpse phagocytosis, and mig-2 and rac-2 have only subtle roles in this process. Rac activators are also used differentially. The UNC-73 Trio Rac GTP exchange factor affected all Rac pathways in axon pathfinding and cell migration but did not affect cell-corpse phagocytosis. CED-5 DOCK180, which acts with CED-10 Rac in cell-corpse phagocytosis, acted with MIG-2 but not CED-10 in axon pathfinding. Thus, distinct regulatory proteins modulate Rac activation and function in different developmental processes.

scholarly journals Tuberin levels during cellular differentiation in brain development

2021 ◽  
Author(s):  
Bashaer Abu Khatir ◽  
Gordon Omar Davis ◽  
Mariam Sameem ◽  
Rutu Patel ◽  
Jackie Fong ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Development ◽  
Cell Lines ◽  
Neural Development ◽  
Time Course ◽  
Embryonic Mouse ◽  
Organ Systems ◽  
The Central Nervous System

Tuberin is a member of a large protein complex, Tuberous Sclerosis Complex, and acts as a sensor for nutrient status regulating protein synthesis and cell cycle progression. Mutations in the Tuberin gene, TSC2, lead to the formation of tumors and developmental defects in many organ systems, including the central nervous system. Tuberin is expressed in the brain throughout development and levels of Tuberin have been found to decrease during neuronal differentiation in cell lines in vitro. Our current work investigates the levels of Tuberin at two stages of embryonic development in vivo, and we study the mRNA and protein levels during a time course using immortalized cell lines in vitro. Our results show that Tuberin levels remain stable in the olfactory bulb but decrease in the Purkinje cell layer during embryonic mouse brain development. We show here that Tuberin levels are higher when cells are cultured as neurospheres, and knockdown of Tuberin results in a reduction in the number of neurospheres. These data provide support for the hypothesis that Tuberin is an important regulator of stemness and the reduction of Tuberin levels might support functional differentiation in the central nervous system. Understanding how Tuberin expression is regulated throughout neural development is essential to fully comprehend the role of this protein in several developmental and neural pathologies.

Limb weakness

2015 ◽  
Author(s):  
Hugo Farne ◽  
Edward Norris-Cervetto ◽  
James Warbrick-Smith
Keyword(s):  
Motor Neurons ◽  
Time Course ◽  
Internal Capsule ◽  
Time Frame ◽  
Rapid Onset ◽  
Sudden Onset ◽  
Limb Weakness ◽  
Ischaemic Attack ◽  
Definition Of ◽  
Slow Growing

The definition of weakness is important, because many patients who self-describe a ‘weak limb’ will actually have a clumsy limb (ataxia), a numb limb (reduced sensation), or a limb that is too painful to move. The time course of the onset of the symptoms in general reflects the time course of the underlying pathology: • Sudden onset (seconds to minutes) usually implies either trauma (e.g. displaced vertebral fractures due to major trauma) or certain vascular insults (e.g. stroke, transient ischaemic attack (TIA)). • Subacute onset (hours to days) suggests a progressive demyelination (e.g. Guillain–Barre syndrome, multiple sclerosis) or a slowly expanding haematoma (e.g. subdural haematoma). • Chronic onset (weeks to months), is consistent with pathologies such as a slow-growing tumour or motor neuron disease (progressive degeneration of motor neurons). As only acute and subacute limb weakness will present acutely to generalists in hospital (chronic onset cases will most likely be referred to neurology from primary care), we have limited the chapter to these cases. Limb movement requires an intact pathway from the cerebral cortex, down the corona radiata, internal capsule, and pons, along the corticospinal tract of the spinal cord, out along a nerve root, and down a peripheral nerve to the neuromuscular junction and muscle itself. If a patient has limb weakness, there must be a lesion somewhere in this pathway. Figure 26.2 gives the differential diagnosis for limb weakness. Mr Walker has presented with rapid onset of left-sided arm weakness. Key clues in the history to elicit include: • Exact time of onset? This is critical in suspected strokes because the window of time in which to confirm the diagnosis and administer thrombolysis (if appropriate) is only 4.5 hours from onset of symptoms (after that, you risk doing more harm than good to the patient). If you suspect a stroke in a patient within that time frame, call the thrombolysis team immediately. In this case, all we can say is that the onset was at some point in the 7 hours between 11 p.m. (when he went to sleep) and 6 a.m. (when he woke up), so we cannot confidently say the onset was within 4.5 hours.

scholarly journals Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model

2020 ◽  
Vol 48 (6) ◽  
pp. 2853-2865 ◽  
Author(s):  
Lei Sheng ◽  
Frank Rigo ◽  
C Frank Bennett ◽  
Adrian R Krainer ◽  
Yimin Hua
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Time Course ◽  
Neuromuscular Junctions ◽  
Muscular Atrophy ◽  
Body Weight Gain ◽  
Target Sequence ◽  
Advantages And Disadvantages ◽  
Extended Target ◽  
The Central Nervous System

Abstract Spinal muscular atrophy (SMA) is a motor neuron disease. Nusinersen, a splice-switching antisense oligonucleotide (ASO), was the first approved drug to treat SMA. Based on prior preclinical studies, both 2′-O-methoxyethyl (MOE) with a phosphorothioate backbone and morpholino with a phosphorodiamidate backbone—with the same or extended target sequence as nusinersen—displayed efficient rescue of SMA mouse models. Here, we compared the therapeutic efficacy of these two modification chemistries in rescue of a severe mouse model using ASO10-29—a 2-nt longer version of nusinersen—via subcutaneous injection. Although both chemistries efficiently corrected SMN2 splicing in various tissues, restored motor function and improved the integrity of neuromuscular junctions, MOE-modified ASO10-29 (MOE10-29) was more efficacious than morpholino-modified ASO10-29 (PMO10-29) at the same molar dose, as seen by longer survival, greater body-weight gain and better preservation of motor neurons. Time-course analysis revealed that MOE10-29 had more persistent effects than PMO10-29. On the other hand, PMO10-29 appears to more readily cross an immature blood-brain barrier following systemic administration, showing more robust initial effects on SMN2 exon 7 inclusion, but less persistence in the central nervous system. We conclude that both modifications can be effective as splice-switching ASOs in the context of SMA and potentially other diseases, and discuss the advantages and disadvantages of each.

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