Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Dev Biol ; 298(1): 118-31, 2006 Oct 01.
Article in English | MEDLINE | ID: mdl-16875686

ABSTRACT

The myelin sheath insulates axons in the vertebrate nervous system, allowing rapid propagation of action potentials via saltatory conduction. Specialized glial cells, termed Schwann cells in the PNS and oligodendrocytes in the CNS, wrap axons to form myelin, a compacted, multilayered sheath comprising specific proteins and lipids. Disruption of myelinated axons causes human diseases, including multiple sclerosis and Charcot-Marie-Tooth peripheral neuropathies. Despite the progress in identifying human disease genes and other mutations disrupting glial development and myelination, many important unanswered questions remain about the mechanisms that coordinate the development of myelinated axons. To address these questions, we began a genetic dissection of myelination in zebrafish. Here we report a genetic screen that identified 13 mutations, which define 10 genes, disrupting the development of myelinated axons. We present the initial characterization of seven of these mutations, defining six different genes, along with additional characterization of mutations that we have described previously. The different mutations affect the PNS, the CNS, or both, and phenotypic analyses indicate that the genes affect a wide range of steps in glial development, from fate specification through terminal differentiation. The analysis of these mutations will advance our understanding of myelination, and the mutants will serve as models of human diseases of myelin.


Subject(s)
Axons/metabolism , Mutation , Myelin Sheath/metabolism , Nerve Fibers, Myelinated/metabolism , Zebrafish Proteins/genetics , Zebrafish/metabolism , Animals , Body Patterning , Central Nervous System/metabolism , Embryo, Nonmammalian , Gene Expression Regulation, Developmental , Male , Peripheral Nervous System/metabolism , Phenotype , Zebrafish/embryology , Zebrafish/genetics , Zebrafish Proteins/metabolism
2.
Curr Biol ; 15(6): 513-24, 2005 Mar 29.
Article in English | MEDLINE | ID: mdl-15797019

ABSTRACT

BACKGROUND: Myelin is critical for efficient axonal conduction in the vertebrate nervous system. Neuregulin (Nrg) ligands and their ErbB receptors are required for the development of Schwann cells, the glial cells that form myelin in the peripheral nervous system. Previous studies have not determined whether Nrg-ErbB signaling is essential in vivo for Schwann cell fate specification, proliferation, survival, migration, or the onset of myelination. RESULTS: In genetic screens for mutants with disruptions in myelinated nerves, we identified mutations in erbb3 and erbb2, which together encode a heteromeric tyrosine kinase receptor for Neuregulin ligands. Phenotypic analysis shows that both genes are essential for development of Schwann cells. BrdU-incorporation studies and time-lapse analysis reveal that Schwann cell proliferation and migration, but not survival, are disrupted in erbb3 mutants. We show that Schwann cells can migrate in the absence of DNA replication. This uncoupling of proliferation and migration indicates that erbb gene function is required independently for these two processes. Pharmacological inhibition of ErbB signaling at different stages reveals a continuing requirement for ErbB function during migration and also provides evidence that ErbB signaling is required after migration for proliferation and the terminal differentiation of myelinating Schwann cells. CONCLUSIONS: These results provide in vivo evidence that Neuregulin-ErbB signaling is essential for directed Schwann cell migration and demonstrate that this pathway is also required for the onset of myelination in postmigratory Schwann cells.


Subject(s)
Cell Movement/physiology , Genes, erbB-2/genetics , Genes, erbB/genetics , Myelin Sheath/metabolism , Schwann Cells/metabolism , Signal Transduction/physiology , Zebrafish/physiology , Animals , Aphidicolin/pharmacology , Base Sequence , Bromodeoxyuridine , Cell Division/drug effects , Chromosome Mapping , DNA, Complementary/genetics , Immunohistochemistry , In Situ Hybridization , Molecular Sequence Data , Mutation/genetics , Neuregulin-1/metabolism , Schwann Cells/physiology , Sequence Analysis, DNA , Zebrafish/genetics
3.
Development ; 132(4): 645-58, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15677724

ABSTRACT

In this study, we elucidate the roles of the winged-helix transcription factor Foxa2 in ventral CNS development in zebrafish. Through cloning of monorail (mol), which we find encodes the transcription factor Foxa2, and phenotypic analysis of mol-/- embryos, we show that floorplate is induced in the absence of Foxa2 function but fails to further differentiate. In mol-/- mutants, expression of Foxa and Hh family genes is not maintained in floorplate cells and lateral expansion of the floorplate fails to occur. Our results suggest that this is due to defects both in the regulation of Hh activity in medial floorplate cells as well as cell-autonomous requirements for Foxa2 in the prospective laterally positioned floorplate cells themselves. Foxa2 is also required for induction and/or patterning of several distinct cell types in the ventral CNS. Serotonergic neurones of the raphenucleus and the trochlear motor nucleus are absent in mol-/- embryos, and oculomotor and facial motoneurones ectopically occupy ventral CNS midline positions in the midbrain and hindbrain. There is also a severe reduction of prospective oligodendrocytes in the midbrain and hindbrain. Finally, in the absence of Foxa2, at least two likely Hh pathway target genes are ectopically expressed in more dorsal regions of the midbrain and hindbrain ventricular neuroepithelium, raising the possibility that Foxa2 activity may normally be required to limit the range of action of secreted Hh proteins.


Subject(s)
Central Nervous System/embryology , Embryonic Induction/physiology , Motor Neurons/cytology , Oligodendroglia/cytology , Transcription Factors/metabolism , Zebrafish Proteins/metabolism , Animals , Central Nervous System/cytology , Central Nervous System/physiology , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/metabolism , Forkhead Transcription Factors , Gene Expression Regulation, Developmental/genetics , Gene Expression Regulation, Developmental/physiology , Hedgehog Proteins , Motor Neurons/metabolism , Mutation/genetics , Oligodendroglia/metabolism , Raphe Nuclei/cytology , Raphe Nuclei/embryology , Raphe Nuclei/metabolism , Serotonin/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/genetics , Trochlear Nerve/cytology , Trochlear Nerve/embryology , Trochlear Nerve/metabolism , Zebrafish/embryology , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...