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1.
Anat Sci Int ; 95(1): 143-152, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31414371

RESUMO

We encountered a fetal pig with eventration of the diaphragm and pulmonary hypoplasia accompanied by phrenic nerve agenesis. The fetal pig was female measuring 34 cm in crown-rump length and about 1500 g in body weight. The diaphragm was a complete continuous sheet, but comprised a translucent membrane with residual muscular tissue only at the dorsolateral area of the right leaf of the diaphragm. The left leaf protruded extraordinarily toward the thoracic cavity. The left phrenic nerve was completely absent, while there was a slight remnant of the right phrenic nerve that supplied the dorsolateral muscular area of the right leaf. Both lungs were small, and the number of smaller bronchioles arising from the bronchioles was decreased to about half of that of the normal lung. Additionally, the right and left subclavius muscles and nerves could not be identified. These findings imply that the diaphragm, the subclavius muscle and nerves innervating them comprise a developmental module, which would secondarily affect lung development. It is considered that the present case is analogous to the animal model of congenital eventration of the diaphragm in humans.


Assuntos
Eventração Diafragmática/embriologia , Nervo Frênico/anormalidades , Nervo Frênico/embriologia , Suínos/embriologia , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/patologia , Animais , Eventração Diafragmática/patologia , Modelos Animais de Doenças , Pulmão/anormalidades , Pulmão/embriologia , Pulmão/patologia , Pneumopatias/embriologia , Pneumopatias/patologia , Nervo Frênico/patologia
2.
Elife ; 62017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28639940

RESUMO

The diaphragm muscle is essential for breathing in mammals. Its asymmetric elevation during contraction correlates with morphological features suggestive of inherent left-right (L/R) asymmetry. Whether this asymmetry is due to L versus R differences in the muscle or in the phrenic nerve activity is unknown. Here, we have combined the analysis of genetically modified mouse models with transcriptomic analysis to show that both the diaphragm muscle and phrenic nerves have asymmetries, which can be established independently of each other during early embryogenesis in pathway instructed by Nodal, a morphogen that also conveys asymmetry in other organs. We further found that phrenic motoneurons receive an early L/R genetic imprint, with L versus R differences both in Slit/Robo signaling and MMP2 activity and in the contribution of both pathways to establish phrenic nerve asymmetry. Our study therefore demonstrates L-R imprinting of spinal motoneurons and describes how L/R modulation of axon guidance signaling helps to match neural circuit formation to organ asymmetry.


Assuntos
Diafragma/embriologia , Diafragma/inervação , Vias Neurais/embriologia , Nervo Frênico/embriologia , Animais , Animais Geneticamente Modificados , Perfilação da Expressão Gênica , Camundongos , Neurônios Motores/fisiologia , Proteína Nodal/metabolismo , Transdução de Sinais
3.
Exp Neurol ; 287(Pt 2): 137-143, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27181410

RESUMO

The review outlines data consistent with the hypothesis that inspiratory drive transmission that generates fetal breathing movements (FBMs) is essential for the developmental plasticity of phrenic motoneurons (PMNs) and diaphragm musculature prior to birth. A systematic examination during the perinatal period demonstrated a very marked transformation of PMN and diaphragm properties coinciding with the onset and strengthening of inspiratory drive and FBMs in utero. This included studies of age-dependent changes of: i) morphology, neuronal coupling, passive and electrophysiological properties of PMNs; ii) rhythmic inspiratory activity in vitro; iii) FBMs generated in vivo detected by ultrasonography; iv) contractile and end-plate potential properties of diaphragm musculature. We also propose how the hypothesis can be further evaluated with studies of perinatal hypoglossal motoneuron-tongue musculature and the use of Dbx1 null mice that provide an experimental model lacking descending inspiratory drive transmission in utero.


Assuntos
Diafragma/fisiologia , Inalação/fisiologia , Neurônios Motores/fisiologia , Plasticidade Neuronal/fisiologia , Nervo Frênico , Animais , Feto , Humanos , Camundongos , Nervo Frênico/citologia , Nervo Frênico/embriologia , Nervo Frênico/crescimento & desenvolvimento
5.
J Neurosci Methods ; 238: 95-104, 2014 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-25251554

RESUMO

Signals from nerve and muscle regulate the formation of synapses. Transgenic mouse models and muscle cell cultures have elucidated the molecular mechanisms required for aggregation and stabilization of synaptic structures. However, far less is known about the molecular pathways involved in redistribution of muscle synaptic components. Here we established a physiologically viable whole-muscle embryonic explant system, in the presence or absence of the nerve, which demonstrates the synaptic landscape is dynamic and malleable. Manipulations of factors intrinsic to the muscle or extrinsically provided by the nerve illustrate vital functions during formation, redistribution and elimination of acetylcholine receptor (AChR) clusters. In particular, RyR1 activity is an important mediator of these functions. This physiologically relevant and readily accessible explant system provides a new approach to genetically uncouple nerve-derived signals and for manipulation via signaling molecules, drugs, and electrical stimulation to examine early formation of the neuromuscular circuit.


Assuntos
Diafragma/embriologia , Diafragma/fisiologia , Sinapses/fisiologia , Animais , Estimulação Elétrica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Imuno-Histoquímica , Camundongos Transgênicos , Nervo Frênico/embriologia , Nervo Frênico/fisiologia , Receptores Colinérgicos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Técnicas de Cultura de Tecidos/métodos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Wnt3A/metabolismo
6.
Development ; 141(4): 784-94, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24496616

RESUMO

Air breathing is an essential motor function for vertebrates living on land. The rhythm that drives breathing is generated within the central nervous system and relayed via specialised subsets of spinal motor neurons to muscles that regulate lung volume. In mammals, a key respiratory muscle is the diaphragm, which is innervated by motor neurons in the phrenic nucleus. Remarkably, relatively little is known about how this crucial subtype of motor neuron is generated during embryogenesis. Here, we used direct differentiation of motor neurons from mouse embryonic stem cells as a tool to identify genes that direct phrenic neuron identity. We find that three determinants, Pou3f1, Hoxa5 and Notch, act in combination to promote a phrenic neuron molecular identity. We show that Notch signalling induces Pou3f1 in developing motor neurons in vitro and in vivo. This suggests that the phrenic neuron lineage is established through a local source of Notch ligand at mid-cervical levels. Furthermore, we find that the cadherins Pcdh10, which is regulated by Pou3f1 and Hoxa5, and Cdh10, which is controlled by Pou3f1, are both mediators of like-like clustering of motor neuron cell bodies. This specific Pcdh10/Cdh10 activity might provide the means by which phrenic neurons are assembled into a distinct nucleus. Our study provides a framework for understanding how phrenic neuron identity is conferred and will help to generate this rare and inaccessible yet vital neuronal subtype directly from pluripotent stem cells, thus facilitating subsequent functional investigations.


Assuntos
Caderinas/metabolismo , Células-Tronco Embrionárias/citologia , Neurônios Motores/citologia , Fator 6 de Transcrição de Octâmero/metabolismo , Nervo Frênico/embriologia , Transdução de Sinais/fisiologia , Animais , Diferenciação Celular/fisiologia , Diafragma/inervação , Citometria de Fluxo , Proteínas de Homeodomínio/metabolismo , Camundongos , Neurônios Motores/fisiologia , Fosfoproteínas/metabolismo , Nervo Frênico/citologia , Protocaderinas , Reação em Cadeia da Polimerase em Tempo Real , Receptores Notch/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição , Transcriptoma
7.
Am J Physiol Lung Cell Mol Physiol ; 304(12): L817-30, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23585229

RESUMO

Hox genes encode transcription factors governing complex developmental processes in several organs. A subset of Hox genes are expressed in the developing lung. Except for Hoxa5, the lack of overt lung phenotype in single mutants suggests that Hox genes may not play a predominant role in lung ontogeny or that functional redundancy may mask anomalies. In the Hox5 paralog group, both Hoxa5 and Hoxb5 genes are expressed in the lung mesenchyme whereas Hoxa5 is also expressed in the tracheal mesenchyme. Herein, we generated Hoxa5;Hoxb5 compound mutant mice to evaluate the relative contribution of each gene to lung development. Hoxa5;Hoxb5 mutants carrying the four mutated alleles displayed an aggravated lung phenotype, resulting in the death of the mutant pups at birth. Characterization of the phenotype highlighted the role of Hoxb5 in lung formation, the latter being involved in branching morphogenesis, goblet cell specification, and postnatal air space structure, revealing partial functional redundancy with Hoxa5. However, the Hoxb5 lung phenotypes were less severe than those seen in Hoxa5 mutants, likely because of Hoxa5 compensation. New specific roles for Hoxa5 were also unveiled, demonstrating the extensive contribution of Hoxa5 to the developing respiratory system. The exclusive expression of Hoxa5 in the trachea and the phrenic motor column likely underlies the Hoxa5-specific trachea and diaphragm phenotypes. Altogether, our observations establish that the Hoxa5 and Hoxb5 paralog genes shared some functions during lung morphogenesis, Hoxa5 playing a predominant role.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Pulmão/metabolismo , Morfogênese/genética , Fosfoproteínas/genética , Animais , Diafragma/embriologia , Diafragma/metabolismo , Embrião de Mamíferos , Feminino , Células Caliciformes/metabolismo , Heterozigoto , Proteínas de Homeodomínio/metabolismo , Homozigoto , Pulmão/embriologia , Masculino , Camundongos , Camundongos Transgênicos , Fosfoproteínas/metabolismo , Nervo Frênico/embriologia , Nervo Frênico/metabolismo , Traqueia/embriologia , Traqueia/metabolismo , Fatores de Transcrição
8.
Nat Neurosci ; 15(12): 1636-44, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23103965

RESUMO

Respiration in mammals relies on the rhythmic firing of neurons in the phrenic motor column (PMC), a motor neuron group that provides the sole source of diaphragm innervation. Despite their essential role in breathing, the specific determinants of PMC identity and patterns of connectivity are largely unknown. We show that two Hox genes, Hoxa5 and Hoxc5, control diverse aspects of PMC development including their clustering, intramuscular branching, and survival. In mice lacking Hox5 genes in motor neurons, axons extend to the diaphragm, but fail to arborize, leading to respiratory failure. Genetic rescue of cell death fails to restore columnar organization and branching patterns, indicating these defects are independent of neuronal loss. Unexpectedly, late Hox5 removal preserves columnar organization but depletes PMC number and branches, demonstrating a continuous requirement for Hox function in motor neurons. These findings indicate that Hox5 genes orchestrate PMC development through deployment of temporally distinct wiring programs.


Assuntos
Diafragma/embriologia , Diafragma/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Neurônios Motores/fisiologia , Fosfoproteínas/genética , Sequência de Aminoácidos , Animais , Proteínas de Homeodomínio/antagonistas & inibidores , Proteínas de Homeodomínio/fisiologia , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Neurônios Motores/citologia , Neurogênese/fisiologia , Técnicas de Cultura de Órgãos , Fosfoproteínas/fisiologia , Nervo Frênico/embriologia , Nervo Frênico/fisiologia , Fatores de Transcrição
9.
Adv Exp Med Biol ; 669: 33-6, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20217316

RESUMO

Although the phrenic motoneurons are relatively well-developed at the time of birth as compared to non-respiratory motoneurons, they show distinct anatomical changes during postnatal development. In the present review we summarize anatomical changes of phrenic motoneurons during pre- and postnatal development. Cell bodies of phrenic motoneurons migrate into the ventromedial region of the ventral horn of C3-C6 by E13-E14 in the rat. During development the sizes and surface areas of phrenic motoneurons are increased with changes in dendritic morphology.


Assuntos
Neurônios Motores/citologia , Nervo Frênico/citologia , Nervo Frênico/crescimento & desenvolvimento , Animais , Nervo Frênico/embriologia
10.
J Appl Physiol (1985) ; 104(6): 1818-27, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18403452

RESUMO

At the time of birth, respiratory muscles must be activated to sustain ventilation. The perinatal development of respiratory motor units (comprising an individual motoneuron and the muscle fibers it innervates) shows remarkable features that enable mammals to transition from in utero conditions to the air environment in which the remainder of their life will occur. In addition, significant postnatal maturation is necessary to provide for the range of motor behaviors necessary during breathing, swallowing, and speech. As the main inspiratory muscle, the diaphragm muscle (and the phrenic motoneurons that innervate it) plays a key role in accomplishing these behaviors. Considerable diversity exists across diaphragm motor units, but the determinant factors for this diversity are unknown. In recent years, the mechanisms underlying the development of respiratory motor units have received great attention, and this knowledge may provide the opportunity to design appropriate interventions for the treatment of respiratory disease not only in the perinatal period but likely also in the adult.


Assuntos
Diafragma/crescimento & desenvolvimento , Diafragma/inervação , Neurônios Motores/fisiologia , Desenvolvimento Muscular , Nervo Frênico/crescimento & desenvolvimento , Respiração , Adaptação Fisiológica , Envelhecimento , Animais , Deglutição , Diafragma/embriologia , Humanos , Inalação , Modelos Animais , Junção Neuromuscular/embriologia , Junção Neuromuscular/crescimento & desenvolvimento , Nervo Frênico/embriologia , Fala
11.
J Physiol ; 570(Pt 3): 437-44, 2006 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16284077

RESUMO

By birth, the regulatory neural network responsible for respiratory control is capable of generating robust rhythm-driving ventilation that can adjust to homeostatic needs. The advent of in vitro models isolated from prenatal rodents has significantly advanced our understanding of these processes. In this topical review, we examine the development of medullary respiratory rhythm-generating centres and phrenic motoneurone-diaphragm properties during the prenatal period.


Assuntos
Nervo Frênico/embriologia , Nervo Frênico/fisiologia , Centro Respiratório/embriologia , Centro Respiratório/fisiologia , Mecânica Respiratória/fisiologia , Animais , Feto/fisiologia , Neurônios Motores/fisiologia , Nervo Frênico/citologia , Centro Respiratório/citologia
12.
Folia Morphol (Warsz) ; 64(4): 253-68, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16425151

RESUMO

In three human foetuses aged 15, 17, and 23 weeks the number of axons surrounded by single Schwann cells was counted. These Schwann cell/axon complexes form the Schwann units. The largest Schwann units in the foetus aged 15 weeks contained 232 axons, in the foetus of 17 weeks the number was 140 and in the foetus of 23 weeks the largest units contained 65 axons.


Assuntos
Axônios/ultraestrutura , Feto/anatomia & histologia , Fibras Nervosas Mielinizadas/ultraestrutura , Nervo Frênico/ultraestrutura , Células de Schwann/ultraestrutura , Feminino , Idade Gestacional , Humanos , Nervo Frênico/embriologia , Gravidez
13.
J Neurosci ; 24(36): 7848-58, 2004 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-15356197

RESUMO

The capacity of embryonic stem (ES) cells to form functional motoneurons (MNs) and appropriate connections with muscle was investigated in vitro. ES cells were obtained from a transgenic mouse line in which the gene for enhanced green fluorescent protein (eGFP) is expressed under the control of the promotor of the MN specific homeobox gene Hb9. ES cells were exposed to retinoic acid (RA) and sonic hedgehog agonist (Hh-Ag1.3) to stimulate differentiation into MNs marked by expression of eGFP and the cholinergic transmitter synthetic enzyme choline acetyltransferase. Whole-cell patch-clamp recordings were made from eGFP-labeled cells to investigate the development of functional characteristics of MNs. In voltage-clamp mode, currents, including EPSCs, were recorded in response to exogenous applications of GABA, glycine, and glutamate. EGFP-labeled neurons also express voltage-activated ion channels including fast-inactivating Na(+) channels, delayed rectifier and I(A)-type K(+) channels, and Ca(2+) channels. Current-clamp recordings demonstrated that eGFP-positive neurons generate repetitive trains of action potentials and that l-type Ca(2+) channels mediate sustained depolarizations. When cocultured with a muscle cell line, clustering of acetylcholine receptors on muscle fibers adjacent to developing axons was seen. Intracellular recordings of muscle fibers adjacent to eGFP-positive axons revealed endplate potentials that increased in amplitude and frequency after glutamate application and were sensitive to TTX and curare. In summary, our findings demonstrate that MNs derived from ES cells develop appropriate transmitter receptors, intrinsic properties necessary for appropriate patterns of action potential firing and functional synapses with muscle fibers.


Assuntos
Neurônios Motores/fisiologia , Células-Tronco Pluripotentes/citologia , Acetilcolina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas/fisiologia , Embrião de Galinha , Embrião de Mamíferos/citologia , Regulação da Expressão Gênica , Genes Reporter , Ácido Glutâmico/farmacologia , Glicina/farmacologia , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Proteínas de Homeodomínio/genética , Potenciais da Membrana , Camundongos , Camundongos Transgênicos , Neurônios Motores/citologia , Neurônios Motores/efeitos dos fármacos , Junção Neuromuscular/fisiologia , Junção Neuromuscular/ultraestrutura , Especificidade de Órgãos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Técnicas de Patch-Clamp , Nervo Frênico/embriologia , Nervo Frênico/fisiologia , Regiões Promotoras Genéticas , Ratos , Tetrodotoxina/farmacologia , Fatores de Transcrição/genética , Tretinoína/farmacologia , Ácido gama-Aminobutírico/farmacologia
14.
Proc Natl Acad Sci U S A ; 100(14): 8281-6, 2003 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-12824469

RESUMO

Mice lacking the epidermal growth factor receptor family member ErbB4 exhibit defects in cranial neural crest cell migration but die by embryonic day 11 because of defective heart development. To examine later phenotypes, we rescued the heart defects in ErbB4 mutant mice by expressing ErbB4 under a cardiac-specific myosin promoter. Rescued ErbB4 mutant mice reach adulthood and are fertile. However, during pregnancy, mammary lobuloalveoli fail to differentiate correctly and lactation is defective. Rescued mice also display aberrant cranial nerve architecture and increased numbers of large interneurons within the cerebellum.


Assuntos
Sistema Nervoso Central/embriologia , Nervos Cranianos/embriologia , Receptores ErbB/fisiologia , Lactação/fisiologia , Glândulas Mamárias Animais/anormalidades , Proteínas do Leite , Animais , Diferenciação Celular , Movimento Celular , Cerebelo/anormalidades , DNA Complementar/genética , Proteínas de Ligação a DNA/metabolismo , Desenvolvimento Embrionário e Fetal/genética , Receptores ErbB/deficiência , Receptores ErbB/genética , Feminino , Coração Fetal/crescimento & desenvolvimento , Interneurônios/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Morfogênese/genética , Miosinas/genética , Crista Neural/citologia , Junção Neuromuscular/embriologia , Especificidade de Órgãos , Fosforilação , Nervo Frênico/embriologia , Gravidez , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Receptor ErbB-4 , Fator de Transcrição STAT5 , Transativadores/metabolismo , Transgenes
15.
J Comp Neurol ; 455(4): 477-87, 2003 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-12508321

RESUMO

Textbooks of embryology provide a standard set of drawings and text reflecting the traditional interpretation of phrenic nerve and diaphragm development based on anatomical dissections of embryonic tissue. Here, we revisit this issue, taking advantage of immunohistochemical markers for muscle precursors in conjunction with mouse mutants to perform a systematic examination of phrenic-diaphragm embryogenesis. This includes examining the spatiotemporal relationship of phrenic axon outgrowth and muscle precursors during different stages of myogenesis. Additionally, mutant mice lacking c-met receptors were used to visualize the mesenchymal substratum of the developing diaphragm in the absence of myogenic cells. We found no evidence for contributions to the diaphragm musculature from the lateral body wall, septum transversum, or esophageal mesenchyme, as standard dogma would state. Nor did the data support the hypothesis that the crural diaphragm is of distinct embryological origins. Rather, we found that myogenic cells and axons destined to form the neuromuscular component of the diaphragm coalesce within the pleuroperitoneal fold (PPF). It is the expansion of these components of the PPF that leads to the formation of the diaphragm. Furthermore, we extended these studies to examine the developing diaphragm in an animal model of congenital diaphragmatic hernia (CDH). We find that malformation of the PPF mesenchymal substratum leads to the defect characteristic of CDH. In summary, the data demonstrates that a significant revision of narratives describing normal and pathological development of the diaphragm is warranted.


Assuntos
Diafragma/anormalidades , Hérnia Diafragmática/patologia , Hérnias Diafragmáticas Congênitas , Nervo Frênico/embriologia , Anormalidades do Sistema Respiratório/patologia , Animais , Divisão Celular , Movimento Celular , Diafragma/inervação , Diafragma/patologia , Modelos Animais de Doenças , Hérnia Diafragmática/induzido quimicamente , Camundongos , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/citologia , Éteres Fenílicos , Nervo Frênico/citologia , Proteínas Proto-Oncogênicas c-met/deficiência , Proteínas Proto-Oncogênicas c-met/genética , Ratos , Anormalidades do Sistema Respiratório/genética , Células-Tronco/citologia , Células-Tronco/metabolismo
16.
J Neurobiol ; 46(4): 231-48, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11180152

RESUMO

This study examined the ontogeny of voltage-sensitive calcium conductances in rat phrenic motoneurons (PMNs) and their role in regulating electrical excitability during the perinatal period. Specifically, we studied the period spanning from embryonic day (E)16 through postnatal day (P)1, when PMNs undergo fundamental transformation in their morphology, passive properties, ionic channel composition, synaptic inputs, and electrical excitability. Low voltage-activated (LVA) and high voltage-activated (HVA) conductances were measured using whole cell patch recordings utilizing a cervical slice-phrenic nerve preparation from perinatal rats. Changes between E16 and P0-1 included the following: an approximately 2-fold increase in the density of total calcium conductances, an approximately 2-fold decrease in the density of LVA calcium conductances, and an approximately 3-fold increase in the density of HVA conductances. The elevated expression of T-type calcium channels during the embryonic period lengthened the action potential and enhanced electrical excitability as evidenced by a hyperpolarization-evoked rebound depolarization. The reduction of LVA current density coupled to the presence of a hyperpolarizing outward A-type potassium current had a critical effect in diminishing the rebound depolarization in neonatal PMNs. The increase in HVA current density was concomitant with the emergence of a calcium-dependent "hump-like" afterdepolarization (ADP) and burst-like firing. Neonatal PMNs develop a prominent medium-duration afterhyperpolarization (mAHP) as the result of coupling between N-type calcium channels and small conductance, calcium-activated potassium channels. These data demonstrate that changes in calcium channel expression contribute to the maturation of PMN electrophysiological properties during the time from the commencement of fetal inspiratory drive to the onset of continuous breathing at birth.


Assuntos
Potenciais de Ação/fisiologia , Canais de Cálcio/metabolismo , Diferenciação Celular/fisiologia , Neurônios Motores/metabolismo , Nervo Frênico/embriologia , Medula Espinal/embriologia , Potenciais de Ação/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Feto , Neurônios Motores/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Nervo Frênico/citologia , Nervo Frênico/crescimento & desenvolvimento , Ratos , Ratos Sprague-Dawley , Fenômenos Fisiológicos Respiratórios , Medula Espinal/citologia , Medula Espinal/crescimento & desenvolvimento
17.
Anat Embryol (Berl) ; 202(2): 159-77, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10985434

RESUMO

The development of phrenic motoneurons and descending bulbospinal projections to the cervical spinal cord have been examined in prenatal and early postnatal rats with the aid of the carbocyanine dyes DiI and DiA. Phrenic motoneurons could be identified by retrograde labelling as early as E13, while aggregation of phrenic motoneurons into a column and the formation of dendritic bundles became apparent from E16. The initial phrenic motoneuron dendritic bundles were oriented in the dorsolateral and ventromedial directions, while ventrolaterally directed bundles entering the marginal zone appeared by E16, and rostrocaudal bundles were clearly visible by E21. The column of phrenic motoneurons extended rostrocaudally from C2 to C6 at E13 and E14, but this became confined to the C3-5 segments by E21. Two-way tracing of connections between putative brainstem respiratory centres and cervical spinal cord with the carbocyanine dyes, DiI and DiA, indicated that brainstem bulbospinal neurons in the position of the adult ventral respiratory group (VRG) and medial parabrachial (MPB) nuclei appeared to project to the cervical cord white matter as early as E15 and may contribute axons to the grey matter of the cervical cord as early as E17 These findings are consistent with electrophysiological studies of respiratory function development in the fetal rat, which found relatively regular rhythmic phrenic discharge by E20 to 21. In summary, our findings indicate that the structural differentiation of phrenic motoneurons is well-advanced prior to birth and that the descending pathways involved in the control of respiratory function are in place several days before birth.


Assuntos
Tronco Encefálico/crescimento & desenvolvimento , Nervo Frênico/crescimento & desenvolvimento , Sistema Respiratório/inervação , Animais , Transporte Axonal , Tronco Encefálico/embriologia , Carbocianinas , Dendritos/ultraestrutura , Feminino , Corantes Fluorescentes , Neurônios Motores/fisiologia , Neurônios Motores/ultraestrutura , Vias Neurais/embriologia , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/ultraestrutura , Nervo Frênico/embriologia , Nervo Frênico/ultraestrutura , Gravidez , Compostos de Piridínio , Ratos , Medula Espinal/embriologia , Medula Espinal/crescimento & desenvolvimento
18.
Proc Natl Acad Sci U S A ; 97(3): 1299-304, 2000 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-10655525

RESUMO

Receptor tyrosine kinase erbB2, which is activated by neuregulin, is expressed in Schwann and muscle cells in the developing neuromuscular junction (NMJ). In vitro studies have shown that neuregulin promotes the survival and migration of Schwann cells and stimulates acetylcholine receptor gene transcription in cultured muscle cells. These findings suggest an important role for erbB2 in the development of the NMJ. Here we examine erbB2-deficient mice to determine whether erbB2 is required for NMJ development in vivo. Our analysis shows that there are pre- and postsynaptic defects of developing NMJ in erbB2-deficient embryos. The presynaptic defects include defasciculation and degeneration of the motor nerves, and an absence of Schwann cells. The postsynaptic defect features an impairment of junctional folds at the neuromuscular synapse in the mutants. These results demonstrate that erbB2 is essential for in vivo development of the NMJ.


Assuntos
Axônios/patologia , Regulação da Expressão Gênica no Desenvolvimento , Genes erbB-2 , Neurônios Motores/patologia , Proteínas Musculares/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Junção Neuromuscular/anormalidades , Receptor ErbB-2/fisiologia , Animais , Movimento Celular , Diafragma/embriologia , Diafragma/patologia , Desenvolvimento Embrionário e Fetal , Hibridização in Situ Fluorescente , Músculos Intercostais/embriologia , Músculos Intercostais/patologia , Camundongos , Camundongos Knockout , Camundongos Mutantes Neurológicos , Morfogênese , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Degeneração Neural , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Neurregulinas/fisiologia , Junção Neuromuscular/embriologia , Nervo Frênico/embriologia , Nervo Frênico/patologia , Receptor ErbB-2/deficiência , Receptores Colinérgicos/biossíntese , Receptores Colinérgicos/genética , Células de Schwann/metabolismo , Células de Schwann/patologia
19.
Anat Embryol (Berl) ; 200(6): 625-43, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10592066

RESUMO

The development of the right phrenic nerve and the distribution of phrenic nerve afferents to the spinal cord have been examined with the aid of electron microscopy and carbocyanine dye retrograde diffusion along the phrenic nerve, respectively. The formation of fascicles in the right phrenic nerve commenced at E15, while Schwann cells penetrated the nerve from E17 and myelination began at P0. The total number of axons in the right phrenic nerve decreased from E15 (943, 965 in two animals) to E19 (539, 582), remained steady until P0 (564, 594) before rising to almost adult values by P7 (689, 934). The postnatal rise in number of axons appears to be due to a large influx of unmyelinated axons. Carbocyanine dye tracing revealed that at E13, neurons in dorsal root ganglia C(2) to C(6) contributed peripheral processes to the phrenic nerve. Phrenic afferents arrived in the spinal cord by E13 and penetrated the dorsal horn at E14. Three terminal fields for phrenic afferents became apparent by E17. These were:(1) in the central parts of laminae I to V, (2) medially in laminae V to VII or adjacent area X near the central canal, (3) in laminae VIII and IX, around the differentiating phrenic motoneurons. Around the time of birth, some phrenic afferents in the second group were distributed across the midline and could be seen to approach the ventromedial dendritic bundle of phrenic motoneurons on the contralateral side, but these were no longer seen by P4. Just before birth (E21), afferents in the third group divided into two further subsets, supplying the dorsolateral and ventromedial groups of phrenic motoneuron dendritic bundles, respectively. Our findings strongly suggest that phrenic afferent differentiation is largely complete by birth.


Assuntos
Vias Aferentes/embriologia , Vias Aferentes/crescimento & desenvolvimento , Axônios/ultraestrutura , Nervo Frênico/embriologia , Nervo Frênico/crescimento & desenvolvimento , Medula Espinal/embriologia , Medula Espinal/crescimento & desenvolvimento , Vias Aferentes/ultraestrutura , Animais , Tamanho Celular , Vértebras Cervicais/embriologia , Vértebras Cervicais/crescimento & desenvolvimento , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Nervo Frênico/ultraestrutura , Ratos , Ratos Wistar , Medula Espinal/ultraestrutura
20.
Brain Res Dev Brain Res ; 114(2): 217-27, 1999 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-10320761

RESUMO

Experiments were performed in vitro on foetal (embryonic days 18 to 21, E18-21) and newborn rat (postnatal days 0 to 3, P0-3) brainstem spinal cord preparations to analyse the perinatal developmental changes in the effects induced by substance P. Superfusion of the preparations with SP-containing artificial cerebrospinal fluid (aCSF) induced significant increase in the respiratory frequency of newborn rats (10-9 M), whereas concentration up to 10-7 M induced no change in foetal preparations. A whole cell patch clamp approach was used to record intracellularly from phrenic motoneurones. In newborn or E20-21 foetal rats SP-containing aCSF depolarised the phrenic motoneurones, increased their input resistance, reduced the rheobase current and shifted the frequency-intensity curves upward. In E18 foetal rats, no change was evoked by SP. A peptidase inhibitor mixture was used to block the enzymatic degradation of endogenous SP. This mixture was ineffective in changing the respiratory frequency in newborn and foetal preparations. In newborn rat phrenic motoneurones, the peptidase inhibitor mixture induced changes similar to those caused by SP but no change was induced in foetal rats. These results indicate that SP may modulate (i) the activity of the respiratory rhythm generator in newborn but not in foetal rats, and (ii) the activity of phrenic motoneurones at E20, E21 and in newborn rats but not at E18. Results obtained using the peptidase inhibitor mixture suggest that endogenous SP is probably not involved in the control of the respiratory rhythm in the prenatal period, but may influence the activity of the phrenic motoneurones after birth.


Assuntos
Envelhecimento/fisiologia , Tronco Encefálico/efeitos dos fármacos , Desenvolvimento Embrionário e Fetal/fisiologia , Nervo Frênico/fisiologia , Mecânica Respiratória/fisiologia , Medula Espinal/efeitos dos fármacos , Substância P/farmacologia , Animais , Animais Recém-Nascidos , Tronco Encefálico/embriologia , Tronco Encefálico/crescimento & desenvolvimento , Feto , Idade Gestacional , Potenciais da Membrana , Neurônios Motores/fisiologia , Naloxona/farmacologia , Técnicas de Patch-Clamp , Nervo Frênico/embriologia , Nervo Frênico/crescimento & desenvolvimento , Ratos , Mecânica Respiratória/efeitos dos fármacos , Medula Espinal/embriologia , Medula Espinal/crescimento & desenvolvimento
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