Biomedical subjects

D Lederfein

Publications and source records attributed to D Lederfein.

6 recordsLinked to original sources

PubMed1998

Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms.

Long-term plasticity of the central nervous system (CNS) involves induction of a set of genes whose identity is incompletely characterized. To identify candidate plasticity-related genes (CPGs), we conducted an exhaustive screen for genes that undergo induction or downregulation in the hippocampus dentate gyrus (DG) following animal treatment with the potent glutamate analog, kainate. The screen yielded 362 upregulated CPGs and 41 downregulated transcripts (dCPGs). Of these, 66 CPGs and 5 dCPGs are known genes that encode for a variety of signal transduction proteins, transcription factors, and structural proteins. Seven novel CPGs predict the following putative functions: cpg2--a dystrophin-like cytoskeletal protein; cpg4--a heat-shock protein: cpg16--a protein kinase; cpg20--a transcription factor; cpg21--a dual-specificity MAP-kinase phosphatase; and cpg30 and cpg38--two new seven-transmembrane domain receptors. Experiments performed in vitro and with cultured hippocampal cells confirmed the ability of the cpg-21 product to inactivate the MAP-kinase. To test relevance to neural plasticity, 66 CPGs were tested for induction by stimuli producing long-term potentiation (LTP). Approximately one-fourth of the genes examined were upregulated by LTP. These results indicate that an extensive genetic response is induced in mammalian brain after glutamate receptor activation, and imply that a significant proportion of this activity is coinduced by LTP. Based on the identified CPGs, it is conceivable that multiple cellular mechanisms underlie long-term plasticity of the nervous system.

Amino Acid Sequence↗

PubMed1998

Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway.

The expression of tissue plasminogen activator (tPA) is increased during activity-dependent forms of synaptic plasticity. We have found that inhibitors of tPA inhibit the late phase of long-term potentiation (L-LTP) induced by either forskolin or tetanic stimulation in the hippocampal mossy fiber and Schaffer collateral pathways. Moreover, application of tPA enhances L-LTP induced by a single tetanus. Exposure of granule cells in culture to forskolin results in secretion of tPA, elongation of mossy fiber axons, and formation of new, active presynaptic varicosities contiguous to dendritic clusters of the glutamate receptor R1. These structural changes are blocked by tPA inhibitors and induced by application of tPA. Thus, tPA may be critically involved in the production of L-LTP and specifically in synaptic growth.

Animals↗

PubMed1993

A housekeeping type promoter, located in the 3' region of the Duchenne muscular dystrophy gene, controls the expression of Dp71, a major product of the gene.

The 70.8 kDa protein product of the distal part of the giant Duchenne muscular dystrophy (DMD) gene, Dp71, is expressed in many cell types and tissues. Anchored PCR, primer extension and functional analysis of transfected constructs were used to determine the 5' end of the mRNA and characterize the promoter of this major DMD gene product. The 5' untranslated region (5'UTR) of Dp71 is transcribed from a single exon; the promoter does not contain a TATA box, and has a very high GC content and several potential Sp1 binding sites. It is located more than 2000 kb 3' to the muscle and brain type dystrophin promoters and only 150 kb from the 3' end of the gene, suggesting that in most DMD patients the expression of Dp71 is unaffected.

Animals↗

PubMed1992

A 71-kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues.

The known Duchenne muscular dystrophy (DMD) gene products, the muscle- and brain-type dystrophin isoforms, are 427-kDa proteins translated from 14-kilobase (kb) mRNAs. Recently we described a 6.5-kb mRNA that also is transcribed from the DMD gene. Cloning and in vitro transcription and translation of the entire coding region show that the 6.5-kb mRNA encodes a 70.8-kDa protein that is a major product of the DMD gene. It contains the C-terminal and the cysteine-rich domains of dystrophin, seven additional amino acids at the N terminus, and some modifications formed by alternative splicing in the C-terminal domain. It lacks the entire large domain of spectrin-like repeats and the actin-binding N-terminal domain of dystrophin. This protein is the major DMD gene product in brain and other nonmuscle tissues but is undetectable in skeletal muscle extracts.

Amino Acid Sequence↗

PubMed1992

Characterization and cell type distribution of a novel, major transcript of the Duchenne muscular dystrophy gene.

Previously we identified a novel 6.5 kb mRNA transcribed from the Duchenne muscular dystrophy (DMD) gene. This mRNA differs in coding content and tissue distribution from the known muscle type and brain type 14 kb DMD mRNAs which code for dystrophin. The novel transcript shares with dystrophin most of the sequence coding for the cysteine-rich and C-terminal domains. Here we used cDNA cloning to identify the divergence point between the common region and the sequence unique to the novel mRNA at the 5' end of the sequence encoding the cysteine-rich domain of dystrophin. This unique sequence containing the translation initiation site is located in a new exon in the intron between exons 62 and 63 of the dystrophin gene. Using probes containing RNA sequences specific to the novel mRNA, we investigated the expression of this mRNA in various tissues and cell types. The study reveals that this mRNA is the main DMD gene product detectable in a variety of nonmuscle tissues including brain cells. The amount of this mRNA in some tissues is comparable to the amount of dystrophin mRNA in the muscle. The expression of the 6.5 kb mRNA is down-regulated during differentiation of myogenic cells; it is present in small amounts in proliferating myoblasts but is undetected in differentiated muscle cultures depleted of mononucleated cells.

Animals↗

PubMed1992

Multiple products of the Duchenne muscular dystrophy gene.

The gene which is defective in Duchenne Muscular Dystrophy (DMD) extends over 2300 kb of the X chromosome. Its product in the muscle is a 14 kb mRNA encoding a 427 kd rod-shaped protein called dystrophin. A 14 kb transcript encoding a very similar isoform of dystrophin is produced in the brain. The brain 14 kb mRNA is transcribed from the same gene but controlled by a different promoter, located at least 75 kb upstream from the muscle dystrophin promoter. The regulation of these promoters is very stringently controlled. The muscle-type but not the brain-type dystrophin mRNA is found in cloned skeletal muscle cells and its presence is correlated with the appearance of multinucleated fibers. The brain type is expressed in neurons, while in glia cells the muscle-type promoter is active. A third DMD gene transcript which is only 6.5 kb long has been identified. It contains the sequence coding for the C-terminal domain and the cysteine-rich domain of dystrophin but not the large region encoding the spectrin-like repeats and the N-terminal domain. The cell type distribution of this transcript is also very different from that of the two 14 kb mRNA isoforms. It is the major product of the DMD gene in many nonmuscle tissues including brain. Using monoclonal antibodies we have identified a 77 Kd protein which seems to be the translation product of this mRNA. As expected from the distribution of the 6.5 Kb mRNA, this protein is the major DMD gene product detectable in brain and many other nonmuscle tissues; it is undetectable in skeletal muscle but is present in the heart and stomach (as is the 6.5 Kb mRNA).

Base Sequence↗