A5013702468- Neurogenesis and neuroplasticity mechanisms
- Developmental Biology and Gene Regulation
- RNA Research and Splicing
- Hearing, Cochlea, Tinnitus, Genetics
- Axon Guidance and Neuronal Signaling
- Zebrafish Biomedical Research Applications
- Animal Genetics and Reproduction
- Neuroscience and Neuropharmacology Research
- Congenital heart defects research
- Cardiomyopathy and Myosin Studies
- Cellular Mechanics and Interactions
- Adipose Tissue and Metabolism
- Virus-based gene therapy research
- Epigenetics and DNA Methylation
- Acute Myeloid Leukemia Research
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Pancreatic function and diabetes
- Sleep and Wakefulness Research
- MicroRNA in disease regulation
- Cancer-related gene regulation
- RNA Interference and Gene Delivery
- Circadian rhythm and melatonin
- Ubiquitin and proteasome pathways
- Neurogenetic and Muscular Disorders Research
University of Helsinki
2008-2022
Karolinska Institutet
2005
Max Planck Society
1998-2004
Max Planck Institute for Biophysical Chemistry
1998-2004
Institut Cochin
1994-2002
Inserm
1993-2002
Université Paris Cité
1994-2002
Orion Corporation (Finland)
1990-1994
Helsinki University Hospital
1992
Oulu University Hospital
1992
Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, disorder characterized by lymphedema and predisposition myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite well-defined roles hematopoiesis, functions lymphatic vasculature mechanisms which result not characterized. Here, we provided molecular explanation for subset patients with mutations....
Human genomic DNA fragments containing catechol O ‐methyltransferase (COMT) sequences were isolated and the exon‐intron structure analysed by sequencing, PCR comparing to human COMT cDNA sequences. The gene contains six exons, of which exons 1 2 are non‐coding. MB‐ATG S‐ATG codons, responsible for initiation translation membrane‐bound (MB) soluble (S) forms enzyme, located in exon 3. Two distinct COMT‐specific transcripts, 1.3 kb 1.5 kb, detected various tissues cell lines. Different...
Cyclase-associated proteins (CAPs) are highly conserved actin monomer binding present in all eukaryotes. However, the mechanism by which CAPs contribute to dynamics has been elusive. In mammals, situation is further complicated presence of two CAP isoforms whose differences have not characterized. Here, we show that CAP1 widely expressed mouse nonmuscle cells, whereas CAP2 predominant isoform developing striated muscles. cultured NIH3T3 and B16F1 a abundant protein colocalizes with cofilin-1...
Catechol-O-methyltransferase (COMT) cDNA clones were isolated from a human placental library using synthetic oligonucleotides as probes. All four positive contained an open reading frame, which potentially coded for 24.4-kD polypeptide, presumably corresponding to the cytoplasmic form of COMT (S-COMT). In addition S-COMT sequences, two carried extensions in 5' end, 50-amino-acid peptide extending frame. This sequence stretch signal sequence-like hydrophobic amino acids its terminus. The...
Tissue and vessel wall stiffening alters endothelial cell properties contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts development is not known. Here we show that controls lymphatic morphogenesis. Atomic force microscopy measurements in mouse embryos reveal venous (LEC) progenitors experience a decrease substrate upon migration out of the cardinal vein, which induces GATA2-dependent transcriptional program required form first vessels....
The WH2 (WASP homology domain-2) is a small actin monomer-binding motif and found in many proteins that regulate the cytoskeleton, including beta-thymosins, ciboulot, WASP, verprolin/WIP (WASP-interacting protein). In sequence database searches we identified novel mouse protein containing domain its C-terminal region. This gene also shows strong to human MIM (Missing Metastasis), cDNA fragment present non-metastatic but absent metastatic bladder cancer cell lines. Northern blot situ...
ABSTRACT The morphogenetic development of the mammalian inner ear is a complex multistep process, molecular and cellular details which are only beginning to be unraveled. We show here that mouse netrin 1, known involved in axon guidance cell migration central nervous system, also plays critical role during semicircular canal formation. 1 expressed at high levels otic epithelium, cells will come together form fusion plate, prerequisite for formation canals. In mutant mice, plate severely...
Midbrain GABAergic neurons control several aspects of behavior, but regulation their development and diversity is poorly understood. Here, we further refine the midbrain regions active in neurogenesis show correlation with expression transcription factor Gata2. Using tissue-specific inactivation ectopic expression, that Gata2 regulates neuron mouse midbrain, not rhombomere 1, where it needed serotonergic lineage. Without Gata2, all precursors embryonic fail to activate neuron-specific gene...
To investigate the role of glucose transporter expression in whole-body homeostasis, we have created transgenic mice that a 2.0- to 3.5-fold increase GLUT4 level skeletal muscle and heart. This is sufficient significantly improve insulin action reduce basal blood levels streptozotocin-induced diabetic mice. These results provide first evidence direct causality between overall responsiveness.
MIM/MTSS1 is a tissue-specific regulator of plasma membrane dynamics, whose altered expression levels have been linked to cancer metastasis. MIM deforms phosphoinositide-rich membranes through its I-BAR domain and interacts with actin monomers WH2 domain. Recent work proposed that also potentiates Sonic hedgehog (Shh)-induced gene expression. Here, we generated mutant mice found full-length protein dispensable for embryonic development. However, MIM-deficient displayed severe urinary...
Midbrain- and hindbrain-derived GABAergic interneurons are critical for regulation of sleep, respiratory, sensory-motor motivational processes, they implicated in human neurological disorders. However, the precise mechanisms that underlie generation neuron diversity midbrain-hindbrain region poorly understood. Here, we show unique overlapping requirements related bHLH proteins Tal1 Tal2 neurogenesis midbrain. We specifically sequentially activated during midbrain neurogenesis. Similar to...
Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic hindbrain serotonergic pathways controlling motivation, mood, voluntary movements. Such reside both within the nuclei, in adjacent brain structures, including rostromedial laterodorsal tegmental nuclei. Compared to monoaminergic neurons, development, heterogeneity, molecular characteristics of these regulatory poorly understood. We show here that different subgroups associated with nuclei...
Twinfilin is a highly conserved actin monomer-binding protein that regulates cytoskeletal dynamics in organisms from yeast to mammals. In addition the previously characterized mammalian twinfilin-1, second with ∼65% sequence identity twinfilin-1 exists mouse and humans. However, previous studies failed identify any binding activity this (Rohwer, A., Kittstein, W., Marks, F., Gschwendt, M. (1999) Eur. J. Biochem. 263, 518–525). Here we show protein, which named twinfilin-2, indeed an protein....
We have been able to assign the human catechol-O-methyltransferase gene (COMT) chromosome 22q11.2 by using Southern blot analysis of panels somatic cell hybrids and chromosomal in situ hybridization. Furthermore, DNA from blood bone marrow samples a patient with chronic myeloid leukemia (CML), having an extra Philadelphia (Ph<sup>1</sup>) addition one produced reciprocal translocation between chromosomes 9 22, showed increased COMT BCR dosage as compared DNAs originating CML...
Radial glia play key roles in neuronal migration, axon guidance, and neurogenesis during development of the central nervous system. However, molecular mechanisms regulating growth morphology these extended cells are unknown. We show that ABBA, a novel member IRSp53-MIM protein family, is enriched different types radial glia. ABBA binds ATP-actin monomers with high affinity deforms PtdIns(4,5)P(2)-rich membranes vitro through its WH2 IM domains, respectively. In radial-glia-like C6-R cells,...
Abstract Gata2 has essential roles in the development of many organs. During mouse inner ear morphogenesis, it is expressed otic vesicle and surrounding periotic mesenchyme from early on, but no defects null mice have been observed before lethality at embryonic day (E) 10.5. Here, we used conditional gene targeting to reveal role later stages development. We show that critically required E14.5–E15.5 onward for vestibular morphogenesis. Without semicircular ducts fail grow their normal size...
Diverse mechanisms regulate development of GABAergic neurons in different regions the central nervous system. We have addressed roles a proneural gene, Ascl1, and postmitotic selector Gata2, differentiation neuron subpopulations three diencephalic prosomeres: prethalamus (P3), thalamus (P2) pretectum (P1). Although proliferative progenitor populations commonly express they distinct requirements for it promotion cell-cycle exit identity. Subsequently, Gata2 is activated as precursors are...
The enzyme catechol-O-methyltransferase (COMT) catalyzes the inactivation of catechol-containing molecules by methylation. cDNAs for rat and human COMT have recently been cloned recombinant proteins expressed in prokaryotic eukaryotic cells. We describe here structure gene its 5'-flanking sequences. spans at least 13 kb is composed 5 exons, first one noncoding. two ATG codons initiation translation membrane-bound (MB-COMT) soluble (S-COMT) forms reside second exon. expresses mRNA species 1.6...
The human aldolase A pM promoter is active in fast-twitch muscles. To understand the role of different transcription factors which bind to this and determine ones are responsible for its restricted pattern expression, we analyzed several transgenic lines harboring combinations regulatory elements. We show that muscle-specific expression can be achieved without any binding sites myogenic MyoD MEF2 a 64-bp fragment comprising MEF3 motif an NFI site sufficient drive reporter gene some but,...
Inner ear develops from an induced surface ectoderm placode that invaginates and closes to form the otic vesicle, which then undergoes a complex morphogenetic process membranous labyrinth. morphogenesis is severely affected in Gata3 deficient mouse embryos, but onset basis of phenotype has not been known. We show here deficiency leads severe unique abnormalities during invagination. The invagination problems are accompanied often by formation morphological boundary between dorsal ventral cup...
Gata2 and Gata3 belong to the Gata family of transcription factors in vertebrates that bind a consensus "GATA" DNA sequence. The gene is one earliest markers for developing mouse inner ear. Ear morphogenesis blocked Gata3-deficient embryos, whereas nothing was known role Here, we have compared expression patterns during normal ear development investigated their relationship mice where either or has been inactivated. two genes highly overlapping at embryonic day (E)10.5 but becomes...