ABSTRACT
The Abl and Arg tyrosine kinases play fundamental roles in the development and function of the central nervous system. Arg is most abundant in adult mouse brain, especially in synapse-rich regions. arg(-/-) mice develop normally but exhibit multiple behavioral abnormalities, suggesting that arg(-/-) brains suffer from defects in neuronal function. Embryos deficient in both Abl and Arg suffer from defects in neurulation and die before 11 days postcoitum (dpc). Although they divide normally, abl(-/-)arg(-/-) neuroepithelial cells display gross alterations in their actin cytoskeleton. We find that Abl and Arg colocalize with each other and with actin microfilaments at the apical surface of the developing neuroepithelium. Thus, Abl and Arg play essential roles in neurulation and can regulate the structure of the actin cytoskeleton.
Subject(s)
Brain/physiology , Nervous System Malformations/embryology , Neurons/physiology , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-abl/metabolism , Synapses/physiology , Actins/metabolism , Animals , Brain/abnormalities , Brain/embryology , Crosses, Genetic , Cytoskeleton/pathology , Female , Fetal Death , Male , Mental Disorders/embryology , Mental Disorders/genetics , Mental Disorders/physiopathology , Mice , Mice, Knockout , Microtubule-Associated Proteins/metabolism , Neurons/pathology , Protein-Tyrosine Kinases/deficiency , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins c-abl/deficiency , Proto-Oncogene Proteins c-abl/genetics , Recombinant Fusion Proteins/metabolism , Signal Transduction , Thymus Gland/physiologyABSTRACT
Although the activating factor NF-kappa B can be present in the nucleus of many cell types, transcription and rearrangement of the immunoglobulin kappa chain gene is restricted to cells of the B lineage. Part of this specificity is determined by sequences within the major intron of the kappa gene that specifically silence gene expression in non-B cells (T cells and HeLa cells). These sequences are found in a 232-bp fragment located 5' of the NF-kappa B binding sequence of the enhancer. When this fragment is added back upstream of an active NF-kappa B site, it specifically decreases the expression of a linked gene by more than 10-fold in activated T cells but it has no effect on expression in B cells. The kappa silencer region acts in an orientation- and distance-independent manner and appears to be composed of multiple negative elements. The kappa silencer may act to restrict transcription and rearrangement of the C kappa locus to cells of the B lineage.
Subject(s)
Enhancer Elements, Genetic , Gene Expression Regulation , Genes, Immunoglobulin , Immunoglobulin kappa-Chains/genetics , Regulatory Sequences, Nucleic Acid , T-Lymphocytes/physiology , Animals , B-Lymphocytes/physiology , Base Sequence , Cell Line , HeLa Cells , Humans , Introns , Mice , Molecular Sequence DataABSTRACT
The DNA binding subunit of the transcription factor NF-kappa B, p50, has been cloned. p50 appears to be synthesized as a larger protein that is then processed to its functional size. Sequence analysis reveals remarkable homology for over 300 amino acids at the amino-terminal end to the oncogene v-rel, its cellular homolog c-rel, and the Drosophila maternal effect gene dorsal. This establishes NF-kappa B as a member of the rel family of proteins, all of which display nuclear-cytosolic translocation. Protein sequence from the p65 polypeptide has established that it is not encoded in the same mRNA as p50. However, p65 appears homologous to c-rel, suggesting that c-rel may form heterodimers with p50 and rel may include a homodimerization motif.