M. Arbonés - Academia.edu (original) (raw)

Papers by M. Arbonés

Cell death & disease, 2014

In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of ... more In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rat...

Protein Expression in Down Syndrome Brain, 2001

The availability of the DNA sequence of human chromosome 21 (HSA21) is a landmark contribution th... more The availability of the DNA sequence of human chromosome 21 (HSA21) is a landmark contribution that will have an immediate impact on the study of the role of specific genes to Down syndrome (DS). Trisomy 21, full or partial, is a major cause of mental retardation and other phenotypic abnormalities, collectively known as Down syndrome (DS), a disorder affecting 1 in 700 births. The identification of genes on HSA21 and the elucidation of the function of the proteins encoded by these genes have been a major challenge for the human genome project and for research in DS. Over 100 of the estimated 300-500 genes of HSA21 have been identified, but the function of most remains largely unknown. It is believed that the overexpression of an unknown number of HSA21 genes is directly or indirectly responsible for the mental retardation and the other clinical features of DS. For this reason, HSA21 genes that are expressed in tissues affected in DS patients are of special interest.

Alzheimer's & Dementia, 2014

Innate Immunity, 1997

Interferon-γ (IFN-γ) is known for its important antiviral activity and other immunomodulatory act... more Interferon-γ (IFN-γ) is known for its important antiviral activity and other immunomodulatory actions. In in vitro studies, this cytokine has also been involved in the control of metallothionein (MT) synthesis. MT is a low molecular weight protein comprised of several isoforms called MT-I to MT-IV; of these, MT-1+11 are widely expressed, whereas MT-III and MT-IV are rather tissue specific. In the present report, we have studied in vivo the role of IFN-γ for a normal liver and brain MT-I+II response to immobilization stress and to an inflammatory process caused by bacterial lipopolysaccharide (LPS, endotoxin), using mice carrying a null mutation in the IFN-γ receptor gene (IFN-γR-/-). Liver MT-I mRNA and MT-(I+II) protein levels during stress of IFN-γR-/- mice were similar to those of the two parental mouse strains used to generate them, namely C57BU6 and 129/Sv mice, and that of the F1 C57BU6 x 129/Sv offspring mice. In contrast, liver MT response to LPS was significantly higher in the IFN-γR-/- mice than in the other strains. MT-I+II response to LPS was also higher in IFN-γR-/- mice in medulla plus pons and tended to in hypothalamus, hippocampus, and cerebellum, but not in the remaining brain. These results suggest that a role of IFN-γ on liver and brain MT-I+II response to stress is unlikely, but that this cytokine exerts an inhibitory effect on the signaling pathways activated by LPS involved in MT-I+II regulation. In situ hybridization analysis for MT-I and MT-III mRNAs of control mice revealed significant effects of the functional IFN-γ deficiency on MT-I but not MT-III mRNA levels in the dentate gyrus and the habenula, while no effects were observed in the remaining brain areas studied.

Trends in Molecular Medicine, 2002

International Journal of Developmental Neuroscience, 2008

Neurogenetics, 2003

Otospiralin is a novel protein of unknown function that is produced by non-sensory cells (fibrocy... more Otospiralin is a novel protein of unknown function that is produced by non-sensory cells (fibrocytes) of the inner ear (cochlea and vestibule). We showed that downregulation of otospiralin in guinea pigs leads to deafness and we therefore hypothesized that genetic defects in the otospiralin gene could also cause deafness in humans. In this study, we cloned and localized OTOSP, the human gene for otospiralin. OTOSP spans 1630 nucleotides, contains four exons and codes for a 567-nucleotide cDNA. By fluorescence in situ hybridization and hybrid panel mapping we localized OTOSP on chromosome 2 at position q37.3. There is currently no deafness family linked to this region. We screened OTOSP for mutations in 410 unrelated patients exhibiting various levels of hearing loss. Beside intronic polymorphisms, a rare variant (Pro7Leu) was found in 4 deafness patients and 3 control individuals, indicating that this change is not involved in this condition and excluding OTOSP as a major gene for g...

PLoS ONE, 2009

Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extr... more Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG)-a member of a natural polyphenols family, found in great amount in green tea leaves-is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice.

Physiology & Behavior, 2001

Neurobiology of Disease, 2005

The gene encoding the dual-specificity tyrosine-regulated kinase DYRK1A maps to the chromosomal s... more The gene encoding the dual-specificity tyrosine-regulated kinase DYRK1A maps to the chromosomal segment HSA21q22.2, which lies within the Down syndrome critical region. The reduction in brain size and behavioral defects observed in mice lacking one copy of the murine homologue Dyrk1A (Dyrk1A+/À) support the idea that this kinase may be involved in monosomy 21 associated mental retardation. However, the structural basis of these behavioral defects remains unclear. In the present work, we have analyzed the microstructure of cortical circuitry in the Dyrk1A+/À mouse and control littermates by intracellular injection of Lucifer Yellow in fixed cortical tissue. We found that labeled pyramidal cells were considerably smaller, less branched and less spinous in the cortex of Dyrk1A+/À mice than in control littermates. These results suggest that Dyrk1A influences the size and complexity of pyramidal cells, and thus their capability to integrate information.

Journal of Molecular Medicine, 2002

DFNB8 and DFNB10 phenotypes. To determine the contribution of TMPRSS3 mutations in the general co... more DFNB8 and DFNB10 phenotypes. To determine the contribution of TMPRSS3 mutations in the general congenital/childhood nonsyndromic deaf population we performed mutation analysis of the TMPRSS3 gene in 448 unrelated deaf patients from Spain, Italy, Greece, and Australia who did not have the common 35delG GJB2 mutation. From the 896 chromosomes studied we identified two novel pathogenic mutations accounting for four mutant alleles and at least 16 nonpathogenic sequence variants. The pathogenic mutations were a 1-bp deletion resulting in a frameshift and an amino acid substitution in the LDLRA domain of TMPRSS3. From this and another study we estimate the frequency of TMPRSS3 mutations in our sample as 0.45%, and approximately 0.38% in the general Caucasian childhood deaf population. However, TMPRSS3 is still an important contributor to genetic deafness in populations with large consanguineous families.

Journal of Experimental Medicine, 1995

Leukocyte recruitment into inflammatory sites is initiated by a reversible transient adhesive con... more Leukocyte recruitment into inflammatory sites is initiated by a reversible transient adhesive contact with the endothelium called leukocyte rolling, which is thought to be mediated by the selectin family of adhesion molecules. Selectin-mediated rolling precedes inflammatory cell emigration, which is significantly impaired in both P- and L-selectin gene-deficient mice. We report here that approximately 13% of all leukocytes passing venules of the cremaster muscle of wild-type mice roll along the endothelium at < 20 min after surgical dissection. Rolling leukocyte flux fraction reaches a maximum of 28% at 40-60 min and returns to 13% at 80-120 min. In P-selectin-deficient mice, rolling is absent initially and reaches 5% at 80-120 min. Rolling flux fraction in L-selectin-deficient mice is similar to wild type initially and declines to 5% at 80-120 min. In both wild-type and L-selectin-deficient mice, initial leukocyte rolling (0-60 min) is completely blocked by the P-selectin monocl...

Immunity, 1994

L-selectin, a cell adhesion molecule expressed by leukocytes, mediates the attachment of lymphocy... more L-selectin, a cell adhesion molecule expressed by leukocytes, mediates the attachment of lymphocytes to high endothelial venules (HEV) of peripheral lymph nodes and mediates the earliest interactions between leukocytes and activated vascular endothelium. Mice possessing a mutant L-selectin gene that results in the complete loss of cell surface receptor expression were generated by gene targeting. Lymphocytes from these mice did not bind to peripheral lymph node HEV and these mice had a severe reduction in the number of lymphocytes localized to peripheral lymph nodes. Short-term homing experiments demonstrated that L-selectin was also involved in lymphocyte migration to mucosal lymph nodes, Peyer's patches, and spleen. Furthermore, significant defects in leukocyte rolling and neutrophil migration into the peritoneum in response to an inflammatory stimulus were observed. Thus, L-selectin plays an essential role in leukocyte homing to lymphoid tissues and sites of inflammation.

Human Mutation, 2001

Pendred syndrome is an autosomal-recessive disorder characterized by congenital sensorineural hea... more Pendred syndrome is an autosomal-recessive disorder characterized by congenital sensorineural hearing loss combined with goiter. This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS/SLC26A4) has been mapped to chromosome 7q22-q31 and encodes a chloride-iodide transport protein. Mutations in this gene are also a cause of non-syndromic autosomal recessive hearing impairment (DFNB4). We have analyzed the PDS/SLC26A4 gene in Spanish and Italian families and we have detected five new mutations (X871M, T132I, IVS1-2A>G, Y556H and 406del5).

Human Mutation, 1999

Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities o... more Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter). This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS) has ...

Human Molecular Genetics, 2001

Human Genetics, 2002

Mutations in the connexin26 (GJB2) gene account for about half of inherited non-syndromic deafnes... more Mutations in the connexin26 (GJB2) gene account for about half of inherited non-syndromic deafness cases in Western countries. The connexin26 protein is a subunit of gap junctions that form a network of intercellular communication among supporting cells and fibrocytes in the mammalian inner ear. Here we describe functional implications of mutations in the coding region of con-nexin26 genes (M1V, M34T, L90P, R127H, F161S, P173R, and R184P), identified in patients and stably transfected in human HeLa cells. While all mutated connexin26 cDNAs were transcribed, only M34T, L90P, R127H, F161S, and R184P were translated in HeLa cells. Analysis of indirect immunofluorescence showed membranous localization, strong for M34T, L90P, R127H, and very weak for F161S, but no signal corresponding to M1V, P173R and R184P. Tracer coupling experiments revealed diffusion of microinjected neurobiotin into neighbouring cells in the case of M34T and R127H, whereas M1V, L90P, F161S, P173R and R184P mutants did not show intercellular coupling. The results of oligomerisation studies suggested a partly disturbed assembly of hemichannels in M34T and L90P mutants but complete absence of hemichannel formation in the R184P mutant. The R127H mutation did not affect channel formation and is likely to represent a polymorphism. Our results show that mutations in the connexin26 gene can affect gap junctional intercellular communication at the level of protein translation, trafficking or assembly of hemichannels.