Laura Klesse

Neurotrophins use the Erk5 pathway to mediate a retrograde survival response

Growth factors synthesized and released by target tissues promote survival and differentiation of innervating neurons. This retrograde signal begins when growth factors bind receptors at nerve terminals. Activated receptors are then endocytosed and transported through the axon to the cell body. Here we show that the mitogen-activated protein kinase (MAPK) signaling pathways used by neurotrophins during retrograde signaling differ from those used following direct stimulation of the cell soma. During retrograde signaling, endocytosed neurotrophin receptors (Trks) activate the extracellular signal-related protein kinase 5 (Erk5) pathway, leading to nuclear translocation of Erk5, phosphorylation of CREB, and enhanced neuronal survival. In contrast, Erk1/2, which mediates nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Thus, the Erk5 pathway has a unique function in retrograde signaling. Differential activation of distinct MAPK pathways may enable an individual growth factor to relay information that specifies the location and the nature of stimulation.Growth factors synthesized and released by target tissues promote survival and differentiation of innervating neurons. This retrograde signal begins when growth factors bind receptors at nerve terminals. Activated receptors are then endocytosed and transported through the axon to the cell body. Here we show that the mitogen-activated protein kinase (MAPK) signaling pathways used by neurotrophins during retrograde signaling differ from those used following direct stimulation of the cell soma. During retrograde signaling, endocytosed neurotrophin receptors (Trks) activate the extracellular signal-related protein kinase 5 (Erk5) pathway, leading to nuclear translocation of Erk5, phosphorylation of CREB, and enhanced neuronal survival. In contrast, Erk1/2, which mediates nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Thus, the Erk5 pathway has a unique function in retrograde signaling. Differential activation of distinct MAPK pathways may enable an individual growth factor to relay information that specifies the location and the nature of stimulation.

Nerve growth factor induces survival and differentiation through two distinct signaling cascades in PC12 cells

Nerve growth factor induces differentiation and survival of rat PC12 pheochromocytoma cells. The activation of the erk cascade has been implicated in transducing the multitude of signals induced by NGF. In order to explore the role of this signaling cascade in NGF mediated survival, differentiation and proliferation, we generated recombinant adenoviruses which express the intermediates of the erk cascade in their wild type, dominant negative and constitutively activated forms. We show that differentiation of PC12 cells requires activity of the ras/erk pathway, whereas inhibition of this pathway had no effect on survival or proliferation. Constitutively active forms of ras, raf and mek induced PC12 cell differentiation, while dominant interfering forms inhibited differentiation. Survival of PC12 cells in serum-free medium did not require activity of the ras/erk pathway. Instead, PI3 Kinase signaling was necessary for PC12 cell survival. Interestingly, constitutively activated versions of raf and mek were able to promote survival, but again this was dependent on activation of PI3 Kinase. Therefore, at least two distinct signaling pathways are required in PC12 cells for mediation of NGF functions.

Trks: Signal transduction and intracellular pathways

The neurotrophin family of growth factors supports survival and differentiation of neurons in the developing vertebrate nervous system by binding activating receptor tyrosine kinases, the Trks. Activation of Trk receptors leads to stimulation of a number of intracellular signaling cascades including, among others, the ras/extracellular regulated kinase (erk) and the phosphatidylinositol‐3 kinase (PI 3 kinase) cascades. Over the past several years, work in several neurotrophin responsive systems has begun to identify the role each of these signaling cascades plays in the cellular response to neurotrophins. It now appears that neurotrophins, in particular nerve growth factor (NGF), mediate their multiple effects through a number of distinct intracellular signaling cascades. In this review, we will overview the evidence implicating specific signaling cascades in aspects of the cellular response to the neurotrophins, specifically in response to activation of TrkA by NGF. Microsc. Res. Tech. 45:210–216, 1999.

Activation of Ras is necessary and sufficient for upregulation of vanilloid receptor type 1 in sensory neurons by neurotrophic factors.

We have analyzed signaling pathways involved in neurotrophic factor (NTF)-induced upregulation of nociceptive properties, specifically vanilloid receptor type 1 (VR1), by adult rat dorsal root ganglion neurons. Upregulation of VR1 by nerve growth factor and glial cell line-derived neurotrophic factor is partially blocked by a MEK inhibitor. Dominant negative Ras, but not Rap, blocks NTF-induced ERK activation and VR1 upregulation. Activated Ras mimics NTF-mediated induction of VR1 in dorsal root ganglion neurons. An inhibitor of phosphatidylinositol 3-kinase, LY294002, also inhibited NTF-induced VR1 upregulation. However, this may at least in part be due to a block of NTF-induced ERK activation. Constitutive simultaneous stimulation of both ERK and phosphatidylinositol 3-kinase is not sufficient for VR1 upregulation. Together, the data suggest that VR1 expression by dorsal root ganglion neurons is regulated by common Ras-dependent pathways.

Childhood medulloblastoma: Current status of biology and treatment

Medulloblastoma, a primitive neuro-ectodermal tumour that arises in the posterior fossa, is the most common malignant brain tumour occurring in childhood. Over the past half century, the long-term survival for children with medulloblastoma has improved remarkably from a certain fatal diagnosis to a cancer that is often curable. Although overall survival for children with non-disseminated and non-anaplastic medulloblastoma can approach 80%, the current multidisciplinary therapeutic approach is not without long-term sequelae. Chemotherapy has improved the long-term survival and allowed for reductions in the amount of radiation given, thereby reducing some of the long-term toxicities. In this review, we describe the current understanding of the basic biology of medulloblastoma and report on the current active chemotherapeutic agents utilized in medulloblastoma therapy. Ultimately, our understanding of the basic biology of medulloblastoma may lead to further advances in therapy by providing targets that are more specific and potentially less toxic.

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8–15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = −0.15, 95% confidence interval −0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval −0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. ClinicalTrials.gov identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). Classification of evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

Pleomorphic Xanthoastrocytoma of Childhood: MR Imaging and Diffusion MR Imaging Features

BACKGROUND AND PURPOSE: Pleomorphic xanthoastrocytomas are rare astrocytic neoplasms of childhood and young adulthood. The purpose of this retrospective review was to evaluate MR imaging features of pediatric pleomorphic xanthoastrocytomas with an emphasis on diffusion MR imaging. MATERIALS AND METHODS: Review of the neuro-oncology data base revealed 11 pediatric patients (range, 4.7–16.1 years) with pleomorphic xanthoastroacytomas with 9 of these patients having preoperative MR imaging available. Six patients had preoperative diffusion MR imaging. Demographics, histopathology slides, conventional imaging characteristics (location, cystic component, hemorrhage, enhancement, vasogenic edema, inner table scalloping), and ADC metrics (mean tumor ADC and tumor to normal brain ADC ratio) were evaluated. RESULTS: Three pleomorphic xanthoastrocytomas had anaplastic features. Ten tumors were supratentorial. Two-thirds (6 of 9) of all tumors were either predominantly cystic or had cystic components, and three-fourths (6 of 8) of the supratentorial tumors had associated inner table scalloping. Seven of the 9 tumors had marked vasogenic edema (>10 mm). Mean tumoral ADC (n = 7) was 912 ± 219 × 10−6 mm2/s (min–max: 617–1189). The tumor to normal brain ADC ratio was 1.14 ± 0.26 (min–max: 0.75–1.47). CONCLUSIONS: Pleomorphic xanthoastrocytoma should be entertained in the differential diagnosis of peripheral supratentorial tumors that appear during childhood. Cysts, inner table scalloping, and marked vasogenic edema are relatively frequent features. Relatively low ADC values and ADC ratios are not uncommon in pleomorphic xanthoastrocytoma.

BDNF activated TrkB/IRR receptor chimera promotes survival of sympathetic neurons through Ras and PI-3 kinase signaling

Insulin receptor‐related receptor (IRR) expression is tightly coupled to the nerve growth factor (NGF) receptor, TrkA, throughout development. Expression of both receptors is primarily localized to neural crest derived sensory and sympathetic neurons. In contrast to TrkA, however, the physiological ligand for IRR is unknown. To analyze the intracellular signaling and potential function of the orphan IRR in neurons, an adenovirus expressing a TrkB/IRR chimeric receptor was used to infect cultured mouse superior cervical ganglion neurons that normally require NGF for survival. Brain derived neurotrophic factor (BDNF)‐activated TrkB/IRR induced neuronal survival. We utilized numerous receptor mutants in order to identify the intracellular domains of IRR necessary for signaling and neuron survival. Finally, we employed adenovirus encoding dominant negative forms of the extracellular signal‐regulated kinase (ERK) signaling cascade to demonstrate that IRR, like TrkA, requires ras activation to promote neuron survival. Therefore, by use of the chimeric TrkB/IRR receptor, we have demonstrated the ability of IRR to elicit activation of signaling cascades resulting in a biological response in superior cervical ganglion (SCG) neurons.

Wilms Tumor in a Child with L-2-hydroxyglutaric Aciduria

We report a male infant with L-2-hydroxyglutaric aciduria and Wilms tumor. L-2-hydroxyglutaric aciduria is a rare, autosomal-recessive, inborn error of metabolism characterized by a variable degree of progressive encephalopathy. Of the fewer than 100 cases reported in the literature, at least 9 patients have developed tumors of the central nervous system. To our knowledge, the present case is the 1st example of an extracranial tumor associated with L-2-hydroxyglutaric aciduria. This observation potentially widens the tumor spectrum in this metabolic disorder and may lead to further insight into the relationship between L-2-hydroxyglutaric acid and cellular transformation.

Intracerebral schwannomas: a rare disease with varying natural history.

Although intracerebral schwannomas are typically regarded as benign intracranial tumors, malignancy and recurrence have been reported among patients harboring such neoplasms. The available literature consists of case reports and small series that present variable characteristics distinguishing these unusual lesions. Little advancement has been made to further the understanding and management of these tumors. The authors present 3 cases from their institution that highlight the difference between typical benign intracerebral schwannomas and histopathological variants that may portend more aggressive behavior. Also provided is a review of the literature in the hope of gaining a better understanding of these rare tumors.