Biomedical subjects

Tõnis Timmusk

Publications and source records attributed to Tõnis Timmusk.

7 recordsLinked to original sources

PubMed2007

Mouse and rat BDNF gene structure and expression revisited.

Brain-derived neurotrophic factor (BDNF) has important functions in the development of the nervous system and in brain plasticity-related processes such as memory, learning, and drug addiction. Despite the fact that the function and regulation of rodent BDNF gene expression have received close attention during the last decade, knowledge of the structural organization of mouse and rat BDNF gene has remained incomplete. We have identified and characterized several mouse and rat BDNF transcripts containing novel 5' untranslated exons and introduced a new numbering system for mouse and rat BDNF exons. According to our results both mouse and rat BDNF gene consist of eight 5' untranslated exons and one protein coding 3' exon. Transcription of the gene results in BDNF transcripts containing one of the eight 5' exons spliced to the protein coding exon and in a transcript containing only 5' extended protein coding exon. We also report the distinct tissue-specific expression profiles of each of the mouse and rat 5' exon-specific transcripts in different brain regions and nonneural tissues. In addition, we show that kainic acid-induced seizures that lead to changes in cellular Ca(2+) levels as well as inhibition of DNA methylation and histone deacetylation contribute to the differential regulation of the expression of BDNF transcripts. Finally, we confirm that mouse and rat BDNF gene loci do not encode antisense mRNA transcripts, suggesting that mechanisms of regulation for rodent and human BDNF genes differ substantially.

Animals↗

PubMed2005

Structure, alternative splicing, and expression of the human and mouse KCNIP gene family.

Potassium channel-interacting proteins (KCNIPs, also named KChIPs) modulate A-type potassium channels and favor their surface expression. In addition, KCNIPs have been shown to interact with presenilins and also to function as transcriptional repressors. Here we describe the structures and alternative splicing of the human and mouse KCNIP genes, including novel splice variants for KCNIP1, KCNIP3, and KCNIP4, and show the expression of different KCNIP mRNAs in various mouse and human tissues and brain regions by RT-PCR. Furthermore, we describe the expression of KCNIP1, KCNIP2, KCNIP3, and KCNIP4 mRNAs in the adult mouse brain with in situ hybridization and show that all KCNIP mRNAs were expressed in the neurons of the mouse brain with specific patterns for each KCNIP. Our results show that alternatively spliced KCNIP mRNAs are expressed differentially and could contribute to the diversity of functions of the KCNIP proteins.

Alternative Splicing↗

PubMed2005

Neuronal K+/Cl- co-transporter (KCC2) transgenes lacking neurone restrictive silencer element recapitulate CNS neurone-specific expression and developmental up-regulation of endogenous KCC2 gene.

The K+/Cl- co-transporter KCC2 maintains the low intracellular chloride concentration required for fast synaptic inhibition and is exclusively expressed in neurones of the CNS. Here, we show that the KCC2 gene (alias SLC12a5) has multiple transcription start sites and characterize the activity of 6.8 kb of mouse KCC2 gene regulatory sequence (spanning 1.4 kb upstream from exon 1 to exon 2) using luciferase reporters. Overexpression of neurone-restrictive silencer factor repressed the reporter activity in vitro, apparently via a neurone restrictive silencer element (NRSE(KCC2)) within intron 1 of the mouse KCC2 gene. In transgenic mice, however, KCC2 reporters with or without deletion of the NRSE(KCC2) were expressed exclusively in neurones and predominantly in the CNS with a similar pattern and developmental up-regulation as endogenous KCC2. Moreover, a third transgene with just a 1.4-kb KCC2 promoter region lacking the NRSE(KCC2)-bearing intron 1 was still expressed predominantly in neural tissues. Thus, developmental up-regulation of the KCC2 gene does not require NRSE(KCC2) and the 1.4-kb KCC2 promoter is largely sufficient for neurone-specific expression of KCC2.

Animals↗

PubMed2003

Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.

Huntingtin protein is mutated in Huntington disease. We previously reported that wild-type but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; ref. 2). Here we show that the neuron restrictive silencer element (NRSE) is the target of wild-type huntingtin activity on BDNF promoter II. Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. We also report that wild-type huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. We conclude that wild-type huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identify a new mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes.

Animals↗

PubMed2003

A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system.

Leucine-rich repeat containing proteins are involved in protein-protein interactions and they regulate numerous cellular events during nervous system development and disease. Here we have isolated and characterized a new four-membered family of genes from human and mouse, named LRRTMs, that encode putative leucine-rich repeat transmembrane proteins. Human and mouse LRRTMs are highly conserved, and orthologous genes exist in other vertebrates but not in invertebrates. All LRRTMs, except LRRTM4, are located in the introns of different alpha-catenin genes, suggesting coevolution of these two gene families. We show by in situ hybridization and RT-PCR that LRRTM mRNAs are predominantly expressed in the nervous system and that each LRRTM possesses a specific, partially nonoverlapping expression pattern. The structure and expression profile of LRRTM mRNAs suggest that they may have a role in the development and maintenance of the vertebrate nervous system.

Amino Acid Sequence↗

PubMed2003

Two novel mammalian Nogo receptor homologs differentially expressed in the central and peripheral nervous systems.

The regenerative capacity of the adult mammalian central nervous system is restricted by the myelinating oligodendrocytes that form a nonpermissive environment for axonal growth. Currently only the Nogo receptor (NgR), in complex with p75(NTR) neurotrophin receptor is known to be involved in this inhibitory signalling in neurons. NgR is a common receptor for the three inhibitory myelin proteins Nogo-A, OMgp, and MAG. Here we describe two novel Nogo receptor gene homologs named NGRL2 and NGRL3 from human and mouse that, like NGR, encode putative leucine-rich repeat containing GPI-anchored proteins. We show by in situ hybridisation and by RT-PCR that NGRL mRNAs are predominantly expressed in the neurons of the embryonic and adult central and peripheral nervous systems, and that they together with NGR possess distinct and partially nonoverlapping expression patterns. We also show that all four members of the reticulon family, including Nogo-A, are widely expressed in the nervous system, and therefore are possible ligands for the NgRLs.

Amino Acid Sequence↗

PubMed2002

Dendritic localization of mammalian neuralized mRNA encoding a protein with transcription repression activities.

Drosophila neurogenic gene neuralized (neu) is required for the maintenance of neuroblast cell fate and differentiation. In the present study we have characterized a mouse and a rat homologue of Drosophila neu. Mammalian neu1 encodes several C-terminal RING zinc finger proteins with one or two neuralized homology repeat (NHR) domains. Mammalian neu1 mRNAs are predominantly expressed in the nervous system and in the skeletal muscle with the highest levels in the adult. In the nervous system neu1 mRNAs are expressed in neurons and dendritically localized in several brain regions, suggesting a role of neu1 in the regulation of synaptic function. Mammalian neu1 isoforms exhibit transcription repression activities that are mediated by NHR domains and regulated by nucleocytoplasmic shuttling. In conclusion, our results suggest that mammalian neu1 is a protein with transcriptional repressor activities involved in the regulation of myo- and neurogenesis.

Amino Acid Sequence↗