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1.
J Neurosci ; 33(38): 15132-44, 2013 Sep 18.
Article in English | MEDLINE | ID: mdl-24048844

ABSTRACT

Dendrite development is controlled by the interplay of intrinsic and extrinsic signals affecting initiation, growth, and maintenance of complex dendrites. Bone morphogenetic proteins (BMPs) stimulate dendrite growth in cultures of sympathetic, cortical, and hippocampal neurons but it was unclear whether BMPs control dendrite morphology in vivo. Using a conditional knock-out strategy to eliminate Bmpr1a and Smad4 in immature noradrenergic sympathetic neurons we now show that dendrite length, complexity, and neuron cell body size are reduced in adult mice deficient of Bmpr1a. The combined deletion of Bmpr1a and Bmpr1b causes no further decrease in dendritic features. Sympathetic neurons devoid of Bmpr1a/1b display normal Smad1/5/8 phosphorylation, which suggests that Smad-independent signaling paths are involved in dendritic growth control downstream of BMPR1A/B. Indeed, in the Smad4 conditional knock-out dendrite and cell body size are not affected and dendrite complexity and number are increased. Together, these results demonstrate an in vivo function for BMPs in the generation of mature sympathetic neuron dendrites. BMPR1 signaling controls dendrite complexity postnatally during the major dendritic growth period of sympathetic neurons.


Subject(s)
Bone Morphogenetic Proteins/metabolism , Dendrites/metabolism , Ganglia, Sympathetic/cytology , Sensory Receptor Cells/cytology , Signal Transduction/physiology , Age Factors , Analysis of Variance , Animals , Animals, Newborn , Archaeal Proteins/metabolism , Bone Morphogenetic Protein Receptors, Type I/deficiency , Bone Morphogenetic Protein Receptors, Type I/genetics , Bone Morphogenetic Proteins/genetics , Cells, Cultured , DNA-Directed DNA Polymerase/metabolism , Embryo, Mammalian , Fluorescent Dyes/metabolism , Gene Expression Regulation, Developmental/genetics , Homeodomain Proteins/metabolism , Imaging, Three-Dimensional , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , Models, Neurological , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Smad4 Protein/deficiency , Smad4 Protein/genetics , Statistics, Nonparametric , Transcription Factors/metabolism
2.
Genesis ; 49(12): 935-41, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21634003

ABSTRACT

We generated transgenic mice bearing a tamoxifen-dependent Cre recombinase expressed under the control of the dopamine-ß-hydroxylase promoter. By crossing to the ROSA26 reporter mice we show that tamoxifen-induced Cre recombinase in adult mice specifically activates ß-galactosidase expression in differentiated noradrenergic neurons of the central and peripheral nervous system. Tamoxifen application in adult mice did not induce ß-galactosidase activity in parasympathetic neurons that transiently express DBH during development. Thus, this transgenic mouse line represents a valuable tool to study gene function in mature noradrenergic neurons by conditional inactivation.


Subject(s)
Adrenergic Neurons/metabolism , Dopamine beta-Hydroxylase/genetics , Mice, Transgenic , Tamoxifen/pharmacology , Adrenergic Neurons/cytology , Animals , Cell Line , Crosses, Genetic , Dopamine beta-Hydroxylase/metabolism , Gene Expression Regulation , Genes, Reporter , Genotype , In Situ Hybridization/methods , Integrases/metabolism , Mice , Models, Animal , Neurons/cytology , Neurons/metabolism , Proteins/genetics , Proteins/metabolism , RNA, Untranslated , Recombination, Genetic , beta-Galactosidase/genetics , beta-Galactosidase/metabolism
3.
Dev Biol ; 355(1): 89-100, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21539825

ABSTRACT

Differentiation of sympathetic neurons is controlled by a group of transcription factors, including Phox2b, Ascl1, Hand2 and Gata3, induced by bone morphogenetic proteins (BMPs) in progenitors located in ganglion primordia at the dorsal aorta. Here, we address the function of the transcription factors AP-2ß and AP-2α, expressed in migrating neural crest cells (NCC) and maintained in sympathetic progenitors and differentiated neurons. The elimination of both AP-2α and AP-2ß results in the virtually complete absence of sympathetic and sensory ganglia due to apoptotic cell death of migrating NCC. In the AP-2ß knockout only sympathetic ganglia (SG) are targeted, leading to a reduction in ganglion size by about 40%, which is also caused by apoptotic death of neural crest progenitors. The conditional double knockout of AP-2α and AP-2ß in sympathetic progenitors and differentiated noradrenergic neurons results in a further decrease in neuron number, leading eventually to small sympathetic ganglion rudiments postnatally. The elimination of AP-2ß also leads to the complete absence of noradrenergic neurons of the Locus coeruleus (LC). Whereas AP-2α/ß transcription factors are in vivo not required for the onset or maintenance of noradrenergic differentiation, their essential survival functions are demonstrated for sympathetic progenitors and noradrenergic neurons.


Subject(s)
Ganglia, Sympathetic/metabolism , Neural Stem Cells/metabolism , Transcription Factor AP-2/metabolism , Animals , Cell Differentiation , Cell Survival , Cells, Cultured , Ganglia, Sensory/metabolism , Gene Expression Regulation, Developmental , Locus Coeruleus/metabolism , Mice , Mice, Knockout , Neural Crest/metabolism , Transcription Factor AP-2/genetics
4.
J Neurosci ; 30(3): 905-15, 2010 Jan 20.
Article in English | MEDLINE | ID: mdl-20089899

ABSTRACT

Neuroblastoma is a pediatric tumor that is thought to arise from autonomic precursors in the neural crest. Mutations in the PHOX2B gene have been observed in familial and sporadic forms of neuroblastoma and represent the first defined genetic predisposition for neuroblastoma. Here, we address the mechanisms that may underlie this predisposition, comparing the function of wild-type and mutant Phox2b proteins ectopically expressed in proliferating, embryonic sympathetic neurons. Phox2b displays a strong antiproliferative effect, which is lost in all Phox2b neuroblastoma variants analyzed. In contrast, an increase in sympathetic neuron proliferation is elicited by Phox2b variants with mutations in the homeodomain when endogenous Phox2b levels are lowered by siRNA-mediated knockdown to mimic the situation of heterozygous PHOX2B mutations in neuroblastoma. The increased proliferation is blocked by Hand2 knockdown and the antiproliferative Phox2b effects are rescued by Hand2 overexpression, implying Hand2 in Phox2b-mediated proliferation control. A Phox2b variant with a nonsense mutation in the homeodomain elicits, in addition, a decreased expression of characteristic marker genes. Together, these results suggest that PHOX2B mutations predispose to neuroblastoma by increasing proliferation and promoting dedifferentiation of cells in the sympathoadrenergic lineage.


Subject(s)
Cell Differentiation/physiology , Cell Proliferation , Ganglia, Sympathetic/cytology , Homeodomain Proteins/physiology , Mutation/physiology , Transcription Factors/physiology , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Brain-Derived Neurotrophic Factor/pharmacology , Bromodeoxyuridine/metabolism , Cell Count/methods , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , Chick Embryo , Embryo, Mammalian , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/genetics , Gene Expression Regulation, Neoplastic/genetics , Green Fluorescent Proteins/genetics , Histones/metabolism , Homeodomain Proteins/chemistry , Homeodomain Proteins/genetics , Immunoprecipitation , Inhibitor of Differentiation Protein 2/genetics , Inhibitor of Differentiation Protein 2/metabolism , Mice , Mice, Inbred C57BL , Neuroblastoma , Neurons , RNA, Small Interfering/pharmacology , Transcription Factors/chemistry , Transcription Factors/genetics , Transcription Factors/metabolism , Tyrosine 3-Monooxygenase/metabolism
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