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Biomedical subjects

Robert B Darnell

Publications and source records attributed to Robert B Darnell.

28 records · Page 2Linked to original sources
PubMed2004

The fragile X mental retardation protein, FMRP, recognizes G-quartets.

Fragile X mental retardation is a disease caused by the loss of function of a single RNA-binding protein, FMRP. Identifying the RNA targets recognized by FMRP is likely to reveal much about its functions in controlling some aspects of memory and behavior. Recent evidence suggests that one of the predominant RNA motifs recognized by the FMRP protein is an intramolecular G-quartet and that the RGG box of FMRP mediates this interaction. Searching databases of mRNA sequence information, as well as compiled sequences of predicted FMRP targets based on biochemical identification, has revealed that many of these predicted FMRP targets contain intramolecular G-quartets. Interestingly, many of the G-quartet containing RNA targets encode proteins involved in neuronal development and synaptic function. Defects in the metabolism of this set of RNAs, presumably in the translation of their protein products, is likely to underlie the behavioral and cognitive changes seen in the disease.

Animals↗
PubMed2004

Neuroimmunology of the paraneoplastic neurological degenerations.

The paraneoplastic neurological degenerations (PNDs) are remarkable examples of naturally occurring tumor immunity in humans. In PND patients, common tumors such as breast, ovarian and lung tumors express proteins normally made exclusively in the brain, eliciting an immune response that successfully suppresses growth of the tumor. This successful anti-tumor response would be expected to go clinically unnoticed by the patient, but the immune cells mediating the response somehow cross into the brain, resulting in an autoimmune attack on neurons and neurological symptoms. Pieces of the mystery of this tumor immune response and neuronal autoimmunity have been assembled, but much more needs to be learned.

Animals↗
PubMed2003

Memory, synaptic translation, and...prions?

Two papers from Kausik Si, Eric Kandel, Susan Lindquist, and colleagues set forth a bold new idea for thinking about the mechanisms underlying the generation and maintenance of long-term memories (Si et al., 2003a, 2003b [this issue of Cell]).

Animals↗
PubMed2003

CLIP identifies Nova-regulated RNA networks in the brain.

Nova proteins are neuron-specific antigens targeted in paraneoplastic opsoclonus myoclonus ataxia (POMA), an autoimmune neurologic disease characterized by abnormal motor inhibition. Nova proteins regulate neuronal pre-messenger RNA splicing by directly binding to RNA. To identify Nova RNA targets, we developed a method to purify protein-RNA complexes from mouse brain with the use of ultraviolet cross-linking and immunoprecipitation (CLIP).Thirty-four transcripts were identified multiple times by Nova CLIP.Three-quarters of these encode proteins that function at the neuronal synapse, and one-third are involved in neuronal inhibition.Splicing targets confirmed in Nova-/- mice include c-Jun N-terminal kinase 2, neogenin, and gephyrin; the latter encodes a protein that clusters inhibitory gamma-aminobutyric acid and glycine receptors, two previously identified Nova splicing targets.Thus, CLIP reveals that Nova coordinately regulates a biologically coherent set of RNAs encoding multiple components of the inhibitory synapse, an observation that may relate to the cause of abnormal motor inhibition in POMA.

3' Untranslated Regions↗
PubMed2003

Nova regulates GABA(A) receptor gamma2 alternative splicing via a distal downstream UCAU-rich intronic splicing enhancer.

Nova is a neuron-specific RNA binding protein targeted in patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia, which is characterized by failure of inhibition of brainstem and spinal motor systems. Here, we have biochemically confirmed the observation that splicing regulation of the inhibitory GABA(A) receptor gamma2 (GABA(A)Rgamma2) subunit pre-mRNA exon E9 is disrupted in mice lacking Nova-1. To elucidate the mechanism by which Nova-1 regulates GABA(A)Rgamma2 alternative splicing, we systematically screened minigenes derived from the GABA(A)Rgamma2 and human beta-globin genes for their ability to support Nova-dependent splicing in transient transfection assays. These studies demonstrate that Nova-1 acts directly on GABA(A)Rgamma2 pre-mRNA to regulate E9 splicing and identify an intronic region that is necessary and sufficient for Nova-dependent enhancement of exon inclusion, which we term the NISE (Nova-dependent intronic splicing enhancer) element. The NISE element (located 80 nucleotides upstream of the splice acceptor site of the downstream exon E10) is composed of repeats of the sequence YCAY, consistent with previous studies of the mechanism by which Nova binds RNA. Mutation of these repeats abolishes binding of Nova-1 to the RNA in vitro and Nova-dependent splicing regulation in vivo. These data provide a molecular basis for understanding Nova regulation of GABA(A)Rgamma2 alternative splicing and suggest that general dysregulation of Nova's splicing enhancer function may underlie the neurologic defects seen in Nova's absence.

Alternative Splicing↗
PubMed2002

RNA logic in time and space.

An EMBO-sponsored workshop entitled "Translational Control in Development and Neurobiology" was held recently in Mallorca, Spain. The talks covered mechanisms of translational regulation, particularly in terms of temporal and spatial regulation, over a wide range of biological systems.

Animals↗
PubMed2002

The TRAP100 component of the TRAP/Mediator complex is essential in broad transcriptional events and development.

The multisubunit TRAP/Mediator complex is a mammalian counterpart of the yeast Mediator that shows diverse coactivation functions. Genetic ablation of the murine TRAP100 component of this complex has revealed that it is not essential for cell viability per se. However, null mutant mice die at an early developmental stage with severe malformations, and cultured TRAP100-deficient cells exhibit attenuated functions of a wide variety of transcriptional activators on ectopic reporters. The TRAP100-deficient TRAP/Mediator complex also lacks TRAP95 and TRAP150 beta/SUR2, which together with TRAP100 may form a submodule, and contains a reduced amount of SRB10/CDK8. Nevertheless, the residual complex shows unaltered binding both to RNA polymerase II and, with the exception of the oncoprotein E1A, to various activators. These findings suggest that TRAP/Mediator is broadly involved in transcription and that a TRAP100-containing submodule plays a secondary role, beyond primary activator interactions and RNA polymerase recruitment by the TRAP complex, in magnifying effects of activators on the general transcriptional machinery.

Abnormalities, Multiple↗