Biomedical subjects

G S Huh

Publications and source records attributed to G S Huh.

8 recordsLinked to original sources

PubMed2001

Neuronal plasticity and cellular immunity: shared molecular mechanisms.

It is becoming evident that neurons express an unusual number of molecules that were originally thought to be specific to immune functions. One such molecule, class I major histocompatibility complex, is required in the activity-dependent refinement and plasticity of connections in the developing and adult central nervous system, demonstrating that molecules can perform critical roles in both systems. Recent studies reveal striking parallels between cellular signaling mechanisms in the immune and nervous systems that may provide unexpected insights into the development, function, and diseases of both systems.

Animals↗

PubMed2000

Functional requirement for class I MHC in CNS development and plasticity.

Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3zeta, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).

Animals↗

PubMed1998

Regulation of class I MHC gene expression in the developing and mature CNS by neural activity.

To elucidate molecular mechanisms underlying activity-dependent synaptic remodeling in the developing mammalian visual system, we screened for genes whose expression in the lateral geniculate nucleus (LGN) is regulated by spontaneously generated action potentials present prior to vision. Activity blockade did not alter expression in the LGN of 32 known genes. Differential mRNA display, however, revealed a decrease in mRNAs encoding class I major histocompatibility complex antigens (class I MHC). Postnatally, visually driven activity can regulate class I MHC in the LGN during the final remodeling of retinal ganglion cell axon terminals. Moreover, in the mature hippocampus, class I MHC mRNA levels are increased by kainic acid-induced seizures. Normal expression of class I MHC mRNA is correlated with times and regions of synaptic plasticity, and immunohistochemistry confirms that class I MHC is present in specific subsets of CNS neurons. Finally, beta2-microglobulin, a cosubunit of class I MHC, and CD3zeta, a component of a receptor complex for class I MHC, are also expressed by CNS neurons. These observations indicate that class I MHC molecules, classically thought to mediate cell-cell interactions exclusively in immune function, may play a novel role in neuronal signaling and activity-dependent changes in synaptic connectivity.

Aging↗

PubMed1997

Control of alternative pre-mRNA splicing by distributed pentameric repeats.

Multiple copies of the hexamer TGCATG have been shown to regulate fibronectin pre-mRNA alternative splicing. GCATG repeats also are clustered near the regulated calcitonin-specific 3' splice site in the rat calcitonin/CGRP gene. Specific mutagenesis of these repeats in calcitonin/CGRP pre-mRNA resulted in the loss of calcitonin-specific splicing, suggesting that the native repeats act to enhance alternative exon inclusion. Mutation of subsets of these elements implies that alternative splicing requires a minimum of two repeats, and that the combination of one intronic and one exonic repeat is necessary for optimal cell-specific splicing. However, multimerized intronic repeats inhibited calcitonin-specific splicing in both the wild-type context and in a transcript lacking endogenous repeats. These results suggest that both the number and distribution of repeats may be important features for the regulation of tissue-specific alternative splicing. Further, RNA containing a single repeat bound cell-specific protein complexes, but tissue-specific differences in protein binding were not detected by using multimerized repeats. Together, these data support a novel model for alternative splicing regulation that requires the cell-specific recognition of multiple, distributed sequence elements.

Alternative Splicing↗

PubMed1994

Regulation of alternative pre-mRNA splicing by a novel repeated hexanucleotide element.

The alternatively spliced exon EIIIB is regulated in a cell type-specific manner in the rat fibronectin gene. Splicing of EIIIB into fibronectin mRNA is dependent on sequences in the intron immediately downstream of EIIIB. We show that a short, highly repeated TGCATG motif in this intron is important for cell type-specific recognition of EIIIB as an exon. This motif enhances usage of the EIIIB 5' splice site; furthermore, this repeated TGCATG sequence can activate an alternatively spliced exon in the unrelated rat preprotachykinin pre-mRNA. Interestingly, this sequence can also be found within cis-acting elements identified previously in other alternatively spliced genes. This short repeated TGCATG motif is therefore a cell type-specific element that, in addition to controlling fibronectin alternative splicing, may participate in the regulation of other alternative RNA processing events.

Alternative Splicing↗

PubMed1994

Polymorphism for ribosomal RNA gene arrangement in the mitochondrial genome of fall rye (Secale cereale L.).

A restriction-fragment-length polymorphism (RFLP) in mitochondrial DNA (mtDNA) was detected between varieties of fall rye (Secale cereale L.) by Southern hybridization with rrn18, the gene encoding the mitochondrial 18S ribosomal RNA. Restriction mapping showed that the RFLP is based on differing numbers of genomic contexts (one vs three) for a recombining-repeat element (the "18S/5S repeat"). From examination of other Secale species, we conclude that the one-context state arose relatively recently, putatively by deletion of two of an ancestral set of three distinct genomic loci containing the mitochondrial 18S/5S repeat. This is consistent with our earlier conclusion that the 18S/5S repeat has probably existed in at least two genomic copies throughout much of the history of the grass family (at least 40 million years). Interestingly, the intervarietal difference in the number of distinct rrn18 loci is not accompanied by a major difference in the number of rrn18 copies per unit mass of mtDNA. This suggests the existence of a mechanism that can compensate rather precisely for differences in mitochondrial gene dosage, perhaps by over-replication or stabilization of specific subgenomic molecules.

Base Sequence↗

PubMed1993

Elements regulating an alternatively spliced exon of the rat fibronectin gene.

We have investigated the regulation of splicing of one of the alternatively spliced exons in the rat fibronectin gene, the EIIIB exon. This 273-nucleotide exon is excluded by some cells and included to various degrees by others. We find that EIIIB is intrinsically poorly spliced and that both its exon sequences and its splice sites contribute to its poor recognition. Therefore, cells which recognize the EIIIB exon must have mechanisms for improving its splicing. Furthermore, in order for EIIB to be regulated, a balance must exist between the EIIIB splice sites and those of its flanking exons. Although the intron upstream of EIIIB does not appear to play a role in the recognition of EIIIB for splicing, the intron downstream contains sequence elements which can promote EIIIB recognition in a cell-type-specific fashion. These elements are located an unusually long distance from the exon that they regulate, more than 518 nucleotides downstream from EIIIB, and may represent a novel mode of exon regulation.

Alternative Splicing↗

PubMed1990

Physical organization of the 18S and 5S ribosomal RNA genes in the mitochondrial genome of rye (Secale cereale L.).

The mitochondrial 18S and 5S ribosomal RNA (rRNA) genes of rye, plus a total of about 90 kilobase pairs of flanking DNA, have been cloned and maps of restriction enzyme cleavage sites have been constructed. Like their homologs from hexaploid wheat, the rye genes are closely linked and are part of a three-copy family of recombining repeats (the "18S/5S repeat"). The rye repeat probably also contains a mitochondrial tRNA(fMet) gene, which the wheat repeat is known to carry. However, despite the overall organizational similarity between the wheat and rye 18S/5S repeats in the immediate vicinity of their coding regions, extensive rearrangement of flanking sequences has taken place during evolutionary divergence of the two species. Our data provide additional support for an emerging picture of plant mitochondrial genomes as evolving much more rapidly in structure than in sequence.

Base Sequence↗