RESUMO
Previously we showed that the hippo pathway transcriptional effectors, YAP and TAZ, are essential for Schwann cells (SCs) to develop, maintain and regenerate myelin . Although TEAD1 has been implicated as a partner transcription factor, the mechanisms by which it mediates YAP/TAZ regulation of SC myelination are unclear. Here, using conditional and inducible knockout mice, we show that TEAD1 is crucial for SCs to develop and regenerate myelin. It promotes myelination by both positively and negatively regulating SC proliferation, enabling Krox20/Egr2 to upregulate myelin proteins, and upregulating the cholesterol biosynthetic enzymes FDPS and IDI1. We also show stage-dependent redundancy of TEAD1 and that non-myelinating SCs have a unique requirement for TEAD1 to enwrap nociceptive axons in Remak bundles. Our findings establish TEAD1 as a major partner of YAP/TAZ in developmental myelination and functional nerve regeneration and as a novel transcription factor regulating Remak bundle integrity.
Assuntos
Bainha de Mielina , Nervos Periféricos , Animais , Camundongos , Regulação da Expressão Gênica , Camundongos Knockout , Bainha de Mielina/metabolismo , Nervos Periféricos/metabolismo , Células de Schwann/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Previously we showed that the hippo pathway transcriptional effectors, YAP and TAZ, are essential for Schwann cells (SCs) to develop, maintain and regenerate myelin (Grove et al., 2017; Grove, Lee, Zhao, & Son, 2020). Although TEAD1 has been implicated as a partner transcription factor, the mechanisms by which it mediates YAP/TAZ regulation of SC myelination are unclear. Here, using conditional and inducible knockout mice, we show that TEAD1 is crucial for SCs to develop and regenerate myelin. It promotes myelination by both positively and negatively regulating SC proliferation, enabling Krox20/Egr2 to upregulate myelin proteins, and upregulating the cholesterol biosynthetic enzymes FDPS and IDI1. We also show stage-dependent redundancy of TEAD1 and that non-myelinating SCs have a unique requirement for TEAD1 to enwrap nociceptive axons in Remak bundles. Our findings establish TEAD1 as a major partner of YAP/TAZ in developmental myelination and functional nerve regeneration and as a novel transcription factor regulating Remak bundle integrity.
RESUMO
Despite more than half a century of hominin fossil discoveries in eastern Africa, the regional environmental context of hominin evolution and dispersal is not well established due to the lack of continuous palaeoenvironmental records from one of the proven habitats of early human populations, particularly for the Pleistocene epoch. Here we present a 620,000-year environmental record from Chew Bahir, southern Ethiopia, which is proximal to key fossil sites. Our record documents the potential influence of different episodes of climatic variability on hominin biological and cultural transformation. The appearance of high anatomical diversity in hominin groups coincides with long-lasting and relatively stable humid conditions from ~620,000 to 275,000 years bp (episodes 1-6), interrupted by several abrupt and extreme hydroclimate perturbations. A pattern of pronounced climatic cyclicity transformed habitats during episodes 7-9 (~275,000-60,000 years bp), a crucial phase encompassing the gradual transition from Acheulean to Middle Stone Age technologies, the emergence of Homo sapiens in eastern Africa and key human social and cultural innovations. Those accumulative innovations plus the alignment of humid pulses between northeastern Africa and the eastern Mediterranean during high-frequency climate oscillations of episodes 10-12 (~60,000-10,000 years bp) could have facilitated the global dispersal of H. sapiens.
RESUMO
Previously we showed that YAP/TAZ promote not only proliferation but also differentiation of immature Schwann cells (SCs), thereby forming and maintaining the myelin sheath around peripheral axons (Grove et al., 2017). Here we show that YAP/TAZ are required for mature SCs to restore peripheral myelination, but not to proliferate, after nerve injury. We find that YAP/TAZ dramatically disappear from SCs of adult mice concurrent with axon degeneration after nerve injury. They reappear in SCs only if axons regenerate. YAP/TAZ ablation does not impair SC proliferation or transdifferentiation into growth promoting repair SCs. SCs lacking YAP/TAZ, however, fail to upregulate myelin-associated genes and completely fail to remyelinate regenerated axons. We also show that both YAP and TAZ are redundantly required for optimal remyelination. These findings suggest that axons regulate transcriptional activity of YAP/TAZ in adult SCs and that YAP/TAZ are essential for functional regeneration of peripheral nerve.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Ciclo Celular/fisiologia , Remielinização/fisiologia , Células de Schwann/fisiologia , Nervo Isquiático/lesões , Transativadores/fisiologia , Animais , Axônios/metabolismo , Proliferação de Células/fisiologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Regeneração Nervosa , Nervo Isquiático/fisiologia , Proteínas de Sinalização YAPRESUMO
Systemic artery-to-pulmonary artery fistula (SA-PAF) is a rare phenomenon that can resemble a filling defect on computed tomography angiography (CTA). SA-PAF can be due to congenital or acquired etiologies and can alter the hemodynamics of the pulmonary circulation, with the most serious reported complication being hemoptysis, requiring embolization. We describe a case of an unusual SA-PAF between the right inferior phrenic artery and the right lower lobe pulmonary artery that mimicked an unprovoked pulmonary embolus (PE) on standard CTA in a patient with cardiomyopathy. This SA-PAF was interpreted on CTA as PE due to the presence of a filling defect, revealing that not all filling defects are PE. SA-PAF should always be considered when the clinical context or the imaging findings are atypical, specifically with an isolated filling defect visualized in the inferior lower lobe pulmonary artery. The false-positive PE was the result of mixing of systemic non-opacified blood with opacified pulmonary arterial blood.
RESUMO
Disseminated peritoneal leiomyomatosis (DPL) is a rare variant of extrauterine leiomyomatosis with reported spontaneous and iatrogenic occurrences. It has been associated with hysterectomy and myomectomy. To our knowledge, reports have not yet substantiated occurrence following uterine artery embolization (UAE), which has become a routine minimally invasive alternative to surgery for the treatment of symptomatic leiomyomata. This report presents the case of a nulliparous premenopausal woman with no other contributory history who presented with DPL 3 years after UAE. The presentation of this patient suggests the potential for a causal relationship between UAE and DPL.
Assuntos
Leiomiomatose/diagnóstico por imagem , Leiomiomatose/terapia , Segunda Neoplasia Primária/diagnóstico por imagem , Embolização da Artéria Uterina/métodos , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/terapia , Adulto , Biópsia , Angiografia por Tomografia Computadorizada , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Imageamento por Ressonância Magnética , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/patologia , Pré-MenopausaRESUMO
Bioresorbable Vascular Scaffolds (BVS) have the potential for adaptive vessel remodeling, restoration of vasomotion, and late luminal enlargement, thus allowing them to circumvent target lesion failures associated with bare metal stents (BMS) and drug-eluting stents (DES). However, recent data has shown a concerning increase in BVS-associated scaffold thrombosis (ScT) compared to DES. Upfront administration of GP IIb/IIIa inhibitors (GPIs) has shown to reduce early stent thrombosis (ST) compared to standard of care in BMS and DES. Since the use of GPIs was limited in BVS studies, the effect of GPIs on the rate of BVS-associated ScT is largely unknown. This is the first study investigating whether a planned use of GPIs during implantation of the Absorb BVS represents a safe and effective strategy in reducing ScT. In a retrospective chart review of 22 patients undergoing PCI with BVS implantation and planned GPI administration, no acute ScT, in-hospital MACE, or in-hospital major/minor bleeding events were observed. Bleeding reduction strategies such as shorter GPI infusion and radial access were implemented. This study provides valuable preliminary evidence on the benefit and safety in using planned GPI administration to reduce the incidence of ScT after implantation of BVS.
Assuntos
Abciximab/administração & dosagem , Implantes Absorvíveis , Doença da Artéria Coronariana/cirurgia , Intervenção Coronária Percutânea/métodos , Glicoproteína IIb da Membrana de Plaquetas/efeitos dos fármacos , Tirofibana/administração & dosagem , Alicerces Teciduais , Idoso de 80 Anos ou mais , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Relação Dose-Resposta a Droga , Stents Farmacológicos , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Following nerve injury, denervated Schwann cells (SCs) convert to repair SCs, which enable regeneration of peripheral axons. However, the repair capacity of SCs and the regenerative capacity of peripheral axons are limited. In the present studies we examined a potential therapeutic strategy to enhance the repair capacity of SCs, and tested its efficacy in enhancing regeneration of dorsal root (DR) axons, whose regenerative capacity is particularly weak. We used male and female mice of a doxycycline-inducible transgenic line to induce expression of constitutively active ErbB2 (caErbB2) selectively in SCs after DR crush or transection. Two weeks after injury, injured DRs of induced animals contained far more SCs and SC processes. These SCs had not redifferentiated and continued to proliferate. Injured DRs of induced animals also contained far more axons that regrew along SC processes past the transection or crush site. Remarkably, SCs and axons in uninjured DRs remained quiescent, indicating that caErbB2 enhanced regeneration of injured DRs, without aberrantly activating SCs and axons in intact nerves. We also found that intraspinally expressed glial cell line-derived neurotrophic factor (GDNF), but not the removal of chondroitin sulfate proteoglycans, greatly enhanced the intraspinal migration of caErbB2-expressing SCs, enabling robust penetration of DR axons into the spinal cord. These findings indicate that SC-selective, post-injury activation of ErbB2 provides a novel strategy to powerfully enhance the repair capacity of SCs and axon regeneration, without substantial off-target damage. They also highlight that promoting directed migration of caErbB2-expressing SCs by GDNF might be useful to enable axon regrowth in a non-permissive environment.SIGNIFICANCE STATEMENT Repair of injured peripheral nerves remains a critical clinical problem. We currently lack a therapy that potently enhances axon regeneration in patients with traumatic nerve injury. It is extremely challenging to substantially increase the regenerative capacity of damaged nerves without deleterious off-target effects. It was therefore of great interest to discover that caErbB2 markedly enhances regeneration of damaged dorsal roots, while evoking little change in intact roots. To our knowledge, these findings are the first demonstration that repair capacity of denervated SCs can be efficaciously enhanced without altering innervated SCs. Our study also demonstrates that oncogenic ErbB2 signaling can be activated in SCs but not impede transdifferentiation of denervated SCs to regeneration-promoting repair SCs.
Assuntos
Axônios , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/patologia , Receptor ErbB-2/genética , Células de Schwann , Raízes Nervosas Espinhais/crescimento & desenvolvimento , Animais , Movimento Celular/genética , Transdiferenciação Celular , Denervação , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Masculino , Camundongos , Camundongos Transgênicos , Compressão Nervosa , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Raízes Nervosas Espinhais/citologiaRESUMO
Nuclear exclusion of the transcriptional regulators and potent oncoproteins, YAP/TAZ, is considered necessary for adult tissue homeostasis. Here we show that nuclear YAP/TAZ are essential regulators of peripheral nerve development and myelin maintenance. To proliferate, developing Schwann cells (SCs) require YAP/TAZ to enter S-phase and, without them, fail to generate sufficient SCs for timely axon sorting. To differentiate, SCs require YAP/TAZ to upregulate Krox20 and, without them, completely fail to myelinate, resulting in severe peripheral neuropathy. Remarkably, in adulthood, nuclear YAP/TAZ are selectively expressed by myelinating SCs, and conditional ablation results in severe peripheral demyelination and mouse death. YAP/TAZ regulate both developmental and adult myelination by driving TEAD1 to activate Krox20. Therefore, YAP/TAZ are crucial for SCs to myelinate developing nerve and to maintain myelinated nerve in adulthood. Our study also provides a new insight into the role of nuclear YAP/TAZ in homeostatic maintenance of an adult tissue.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Bainha de Mielina/metabolismo , Fosfoproteínas/metabolismo , Células de Schwann/fisiologia , Fatores de Transcrição/metabolismo , Aciltransferases , Animais , Proteínas de Ciclo Celular , Diferenciação Celular , Proliferação de Células , Camundongos , Proteínas de Sinalização YAPRESUMO
BACKGROUND: Accurate assessment of cardiac output (CO) is essential for the hemodynamic assessment of aortic valve area (AVA). Estimation of oxygen consumption (VO2) and Thermodilution (TD) is employed in many cardiac catheterization laboratories (CCL) given the historically cumbersome nature of direct continuous VO2 measurement, the "gold standard" for this technique. A portable facemask device simplifies the direct continuous measurement of VO2, allowing for relatively rapid and continuous assessment of CO and AVA. METHODS AND MATERIALS: Seventeen consecutive patients undergoing right heart catheterization had simultaneous determination of CO by both direct continuous and assumed VO2 and TD. Assessments were only made when a plateau of VO2 had occurred. All measurements of direct continuous and assumed VO2, as well as, TD CO were obtained in triplicate. RESULTS: Direct continuous VO2 CO and assumed VO2 CO correlated poorly (R= 0.57; ICC =0.59). Direct continuous VO2 CO and TD CO also correlated poorly (R= 0.51; ICC=0.60). Similarly AVA derived from direct continuous VO2 correlated poorly with those of assumed VO2 (R= 0.68; ICC=0.55) and TD (R=0.66, ICC=0.60). Repeated direct continuous VO2 CO and AVA measurements were extremely correlated and reproducible [(R=0.93; ICC=0.96) and (R=0.99; ICC>0.99) respectively], suggesting that this was the most reliable measurement of CO. CONCLUSIONS: CO calculated from direct continuous VO2 measurement varies substantially from both assumed VO2 and TD based CO, which are widely used in most CCL. These differences may significantly impact the CO and AVA measurements. Furthermore, continuous, rather than average, measurement of VO2 appears to give highly reproducible results.
Assuntos
Valva Aórtica/fisiopatologia , Cateterismo Cardíaco/instrumentação , Débito Cardíaco/fisiologia , Consumo de Oxigênio/fisiologia , Idoso , Idoso de 80 Anos ou mais , Cateterismo Cardíaco/métodos , Feminino , Testes de Função Cardíaca/instrumentação , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Accurate assessment of cardiac output (CO) is essential for the hemodynamic assessment of valvular heart disease. Estimation of oxygen consumption (VO2) and thermodilution (TD) are employed in many cardiac catheterization laboratories (CCL) given the historically cumbersome nature of direct continuous VO2 measurement, the "gold standard" for this technique. A portable facemask device simplifies the direct continuous measurement of VO2, allowing for relatively rapid and continuous assessment of CO. METHODS AND MATERIALS: Thirty consecutive patients undergoing right heart catheterization had simultaneous determination of CO by both direct continuous and assumed VO2 and TD. Assessments were only made when a plateau of VO2 had occurred. All measurements of direct continuous and assumed VO2, as well as, TD CO were obtained in triplicate. RESULTS: Direct continuous VO2 CO and assumed VO2 CO correlated poorly (R=0.57; ICC=0.59). Direct continuous VO2 CO and TD CO also correlated poorly (R=0.51; ICC=0.60). Repeated direct continuous VO2 CO measurements were extremely correlated and reproducible [(R=0.93; ICC=0.96) suggesting that this was the most reliable measurement of CO. CONCLUSIONS: CO calculated from direct continuous VO2 measurement varies substantially from both assumed VO2 and TD based CO, which are widely used in most CCL. These differences may significantly impact the CO measurements. Furthermore, continuous, rather than average, measurement of VO2 appears to give highly reproducible results.
Assuntos
Testes Respiratórios , Débito Cardíaco , Testes de Função Cardíaca/normas , Doenças das Valvas Cardíacas/diagnóstico , Consumo de Oxigênio , Termodiluição/normas , Testes Respiratórios/instrumentação , Cateterismo Cardíaco , Testes de Função Cardíaca/instrumentação , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
Without Focal Adhesion Kinase (FAK), developing murine Schwann cells (SCs) proliferate poorly, sort axons inefficiently, and cannot myelinate peripheral nerves. Here we show that FAK is required for the development of SCs when their basal lamina (BL) is fragmentary, but not when it is mature in vivo. Mutant SCs fail to spread on fragmentary BL during development in vivo, and this is phenocopied by SCs lacking functional FAK on low laminin (LN) in vitro. Furthermore, SCs without functional FAK initiate differentiation prematurely, both in vivo and in vitro. In contrast to their behavior on high levels of LN, SCs lacking functional FAK grown on low LN display reduced spreading, proliferation, and indicators of contractility (i.e., stress fibers, arcs, and focal adhesions) and are primed to differentiate. Growth of SCs lacking functional FAK on increasing LN concentrations in vitro revealed that differentiation is not regulated by G1 arrest but rather by cell spreading and the level of contractile actomyosin. The importance of FAK as a critical regulator of the specific response of developing SCs to fragmentary BL was supported by the ability of adult FAK mutant SCs to remyelinate demyelinated adult nerves on mature BL in vivo. We conclude that FAK promotes the spreading and actomyosin contractility of immature SCs on fragmentary BL, thus maintaining their proliferation, and preventing differentiation until they reach high density, thereby promoting radial sorting. Hence, FAK has a critical role in the response of SCs to limiting BL by promoting proliferation and preventing premature SC differentiation.
Assuntos
Membrana Basal/fisiopatologia , Quinase 1 de Adesão Focal/metabolismo , Bainha de Mielina/patologia , Células de Schwann/metabolismo , Neuropatia Ciática/patologia , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Animais , Diferenciação Celular/genética , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Citometria de Fluxo , Quinase 1 de Adesão Focal/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismoRESUMO
Cajal bands are cytoplasmic channels flanked by appositions where the abaxonal surface of Schwann cell myelin apposes and adheres to the overlying plasma membrane. These appositions contain a dystroglycan complex that includes periaxin and dystrophin-related protein 2 (Drp2). Loss of periaxin disrupts appositions and Cajal bands in Schwann cells and causes a severe demyelinating neuropathy in mouse and human. Here, we investigated the role of mouse Drp2 in apposition assembly and Cajal band function and compared it with periaxin. We show that periaxin and Drp2 are not only both required to form appositions, but they must also interact. Periaxin-Drp2 interaction is also required for Drp2 phosphorylation, but phosphorylation is not required for the assembly of appositions. Drp2 loss causes corresponding increases in Dystrophin family members, utrophin and dystrophin Dp116, although dystroglycan remains unchanged. We also show that all dystroglycan complexes in Schwann cells use the uncleaved form of ß-dystroglycan. Drp2-null Schwann cells have disrupted appositions and Cajal bands, and they undergo focal hypermyelination and concomitant demyelination. Nevertheless, they do not have the short internodal lengths and associated reduced nerve conduction velocity seen in the absence of periaxin, showing that periaxin regulates Schwann cell elongation independent of its role in the dystroglycan complex. We conclude that the primary role of the dystroglycan complex in appositions is to stabilize and limit the radial growth of myelin.
Assuntos
Distroglicanas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Células de Schwann/fisiologia , Animais , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Compressão Nervosa/métodos , Proteínas do Tecido Nervoso/genética , Células de Schwann/citologia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologiaRESUMO
In developing peripheral nerves, differentiating Schwann cells sort individual axons from bundles and ensheath them to generate multiple layers of myelin. In recent years, there has been an increased understanding of the extracellular and intracellular factors that initiate and stimulate Schwann cell myelination, together with a growing appreciation of some of the signaling pathways involved. However, our knowledge of how Schwann cell growth is regulated during myelination is still incomplete. The mammalian target of rapamycin (mTOR) is a core kinase in two major complexes, mTORC1 and mTORC2, that regulate cell growth and differentiation in a variety of mammalian cells. Here we show that elimination of mTOR from murine Schwann cells prevented neither radial sorting nor the initiation of myelination. However, normal postnatal growth of myelinating Schwann cells, both radially and longitudinally, was highly retarded. The myelin sheath in the mutant was much thinner than normal; nevertheless, sheath thickness relative to axon diameter (g-ratio) remained constant in both wild-type and mutant nerves from P14 to P90. Although axon diameters were normal in the mutant at the initiation of myelination, further growth as myelination proceeded was retarded, and this was associated with reduced phosphorylation of neurofilaments. Consistent with thinner axonal diameters and internodal lengths, conduction velocities in mutant quadriceps nerves were also reduced. These data establish a critical role for mTOR signaling in both the longitudinal and radial growth of the myelinating Schwann cell.
Assuntos
Axônios/patologia , Bainha de Mielina/patologia , Células de Schwann/patologia , Serina-Treonina Quinases TOR/deficiência , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Crescimento Celular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Bainha de Mielina/genética , Bainha de Mielina/ultraestrutura , Técnicas de Cultura de Órgãos , Células de Schwann/metabolismo , Células de Schwann/ultraestrutura , Serina-Treonina Quinases TOR/genéticaRESUMO
Reduced reproduction increases storage and extends lifespan in several animal species. The disposable soma hypothesis suggests this life extension occurs by shifting allocation of ingested nutrients from reproduction to the soma. A great deal of circumstantial evidence supports this hypothesis, but no direct tracking of nutrients has been performed in animals that are long-lived because of direct reduction in reproduction. Here, we use the stable isotopes to track carbon and nitrogen from ingestion to somatic organs in long-lived, ovariectomized grasshoppers. Three estimates of somatic storage (viz., quantity of hemolymph storage proteins, amount of femur muscle carbohydrates, and size of the fat body) all doubled upon ovariectomy. In stark contrast, ovariectomy did not increase the proportion of these tissues that were made from recently ingested foods. In other words, the physiology underlying relative allocation to these somatic tissues was not affected by ovariectomy. Thus, at the level of whole tissue storage, these results are consistent with a trade-off between reproduction and longevity. In contrast, our stable isotope data are inconsistent with the prediction that enhanced storage in ovariectomized females results from a physiological shift in allocation of ingested nutrients.
Assuntos
Ingestão de Energia/fisiologia , Fertilidade/fisiologia , Gafanhotos/fisiologia , Proteínas de Insetos/biossíntese , Longevidade/fisiologia , Ovariectomia , Animais , Carboidratos/análise , Isótopos de Carbono/análise , Corpo Adiposo/química , Corpo Adiposo/metabolismo , Comportamento Alimentar/fisiologia , Feminino , Alimentos , Hemolinfa/química , Hemolinfa/metabolismo , Espectrometria de Massas , Músculos/química , Músculos/metabolismo , Isótopos de Nitrogênio/análise , Reprodução/fisiologiaRESUMO
All but the smallest-diameter axons in the central nervous system are myelinated, but the signals that initiate myelination are unknown. Our prior work has shown that integrin signaling forms part of the cell-cell interactions that ensure only those oligodendrocytes contacting axons survive. Here, therefore, we have asked whether integrins regulate the interactions that lead to myelination. Using homologous recombination to insert a single-copy transgene into the hypoxanthine phosphoribosyl transferase (hprt) locus, we find that mice expressing a dominant-negative beta1 integrin in myelinating oligodendrocytes require a larger axon diameter to initiate timely myelination. Mice with a conditional deletion of focal adhesion kinase (a signaling molecule activated by integrins) exhibit a similar phenotype. Conversely, transgenic mice expressing dominant-negative beta3 integrin in oligodendrocytes display no myelination abnormalities. We conclude that beta1 integrin plays a key role in the axoglial interactions that sense axon size and initiate myelination, such that loss of integrin signaling leads to a delay in myelination of small-diameter axons.
Assuntos
Integrina beta1/fisiologia , Bainha de Mielina , Oligodendroglia/ultraestrutura , Animais , Axônios , Comunicação Celular , Sistema Nervoso Central/citologia , Hipoxantina Fosforribosiltransferase/genética , Integrina beta3/fisiologia , Integrinas/fisiologia , Camundongos , Camundongos TransgênicosRESUMO
Signaling by laminins and axonal neuregulin has been implicated in regulating axon sorting by myelin-forming Schwann cells. However, the signal transduction mechanisms are unknown. Focal adhesion kinase (FAK) has been linked to alpha6beta1 integrin and ErbB receptor signaling, and we show that myelination by Schwann cells lacking FAK is severely impaired. Mutant Schwann cells could interdigitate between axon bundles, indicating that FAK signaling was not required for process extension. However, Schwann cell FAK was required to stimulate cell proliferation, suggesting that amyelination was caused by insufficient Schwann cells. ErbB2 receptor and AKT were robustly phosphorylated in mutant Schwann cells, indicating that neuregulin signaling from axons was unimpaired. These findings demonstrate the vital relationship between axon defasciculation and Schwann cell number and show the importance of FAK in regulating cell proliferation in the developing nervous system.