Biomedical subjects

Mario Cáceres

Publications and source records attributed to Mario Cáceres.

13 recordsLinked to original sources

PubMed2006

Increased cortical expression of two synaptogenic thrombospondins in human brain evolution.

Thrombospondins are extracellular-matrix glycoproteins implicated in the control of synaptogenesis and neurite growth. Previous microarray studies suggested that one gene of this family, thrombospondin 4 (THBS4), was upregulated during human brain evolution. Using independent techniques to examine thrombospondin expression patterns in adult brain samples, we report approximately 6-fold and approximately 2-fold greater expression of THBS4 and THBS2 messenger RNA (mRNA), respectively, in human cerebral cortex compared with chimpanzees and macaques, with corresponding differences in protein levels. In humans and chimpanzees, thrombospondin expression differences were observed in the forebrain (cortex and caudate), whereas the cerebellum and most nonbrain tissues exhibited similar levels of the 2 mRNAs. Histological examination revealed THBS4 mRNA and protein expression in numerous pyramidal and glial cells in the 3 species but humans also exhibited very prominent immunostaining of the synapse-rich cortical neuropil. In humans, additionally, THBS4 antibodies labeled beta-amyloid containing plaques in Alzheimer's cases and some control cases. This is the first detailed characterization of gene-expression changes in human evolution that involve specific brain regions, including portions of cerebral cortex. Increased expression of thrombospondins in human brain evolution could result in changes in synaptic organization and plasticity, and contribute to the distinctive cognitive abilities of humans, as well as to our unique vulnerability to neurodegenerative disease.

Adult↗

PubMed2006

Novel roles for metallothionein-I + II (MT-I + II) in defense responses, neurogenesis, and tissue restoration after traumatic brain injury: insights from global gene expression profiling in wild-type and MT-I + II knockout mice.

Traumatic injury to the brain is one of the leading causes of injury-related death or disability, especially among young people. Inflammatory processes and oxidative stress likely underlie much of the damage elicited by injury, but the full repertoire of responses involved is not well known. A genomic approach, such as the use of microarrays, provides much insight in this regard, especially if combined with the use of gene-targeted animals. We report here the results of one of these studies comparing wild-type and metallothionein-I + II knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8, and 16 days postlesion (dpl) using Affymetrix genechips/oligonucleotide arrays interrogating approximately 10,000 different murine genes (MG_U74Av2). Hierarchical clustering analysis of these genes readily shows an orderly pattern of gene responses at specific times consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma, as well as a prominent effect of MT-I + II deficiency. The results thoroughly confirmed the importance of the antioxidant proteins MT-I + II in the response of the brain to injury and opened new avenues that were confirmed by immunohistochemistry. Data in KO, MT-I-overexpressing, and MT-II-injected mice strongly suggest a role of these proteins in postlesional activation of neural stem cells.

Analysis of Variance↗

PubMed2006

The gene of retroviral origin Syncytin 1 is specific to hominoids and is inactive in Old World monkeys.

Syncytin 1 is one of the best known examples of recent acquisition of a new gene from an endogenous retrovirus (HERV) in the human genome and has been implicated in placental physiology. Within primates, Syncytin 1 is conserved in all hominoids but has not been characterized in Old World monkeys (OWMs). In this study, we investigated the status of Syncytin 1 in 14 hominoid and OWM species. We show that although the HERV-W provirus responsible for the origin of this gene was present in the genome of the most recent common ancestor of hominoids and OWMs, Syncytin 1 is inactive in OWMs. In addition, we were able to determine that the evolution of Syncytin 1 in hominoids involved an accumulation of amino acid changes and showed signatures of both positive and purifying selection. Our results indicate that Syncytin 1 is indeed a hominoid-specific gene and illustrate the complex and dynamic process associated with the origin of new genes.

Animals↗

PubMed2005

Molecular characterization and chromosomal distribution of Galileo, Kepler and Newton, three foldback transposable elements of the Drosophila buzzatii species complex.

Galileo is a foldback transposable element that has been implicated in the generation of two polymorphic chromosomal inversions in Drosophila buzzatii. Analysis of the inversion breakpoints led to the discovery of two additional elements, called Kepler and Newton, sharing sequence and structural similarities with Galileo. Here, we describe in detail the molecular structure of these three elements, on the basis of the 13 copies found at the inversion breakpoints plus 10 additional copies isolated during this work. Similarly to the foldback elements described in other organisms, these elements have long inverted terminal repeats, which in the case of Galileo possess a complex structure and display a high degree of internal variability between copies. A phylogenetic tree built with their shared sequences shows that the three elements are closely related and diverged approximately 10 million years ago. We have also analyzed the abundance and chromosomal distribution of these elements in D. buzzatii and other species of the repleta group by Southern analysis and in situ hybridization. Overall, the results suggest that these foldback elements are present in all the buzzatti complex species and may have played an important role in shaping their genomes. In addition, we show that recombination rate is the main factor determining the chromosomal distribution of these elements.

Animals↗

PubMed2005

Brain response to traumatic brain injury in wild-type and interleukin-6 knockout mice: a microarray analysis.

Traumatic injury to the brain is one of the leading causes of injury-related death or disability. Brain response to injury is orchestrated by cytokines, such as interleukin (IL)-6, but the full repertoire of responses involved is not well known. We here report the results obtained with microarrays in wild-type and IL-6 knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8 and 16 days post-lesion. Overall gene expression was analyzed by using Affymetrix genechips/oligonucleotide arrays with approximately 12,400 probe sets corresponding to approximately 10,000 different murine genes (MG_U74Av2). A robust, conventional statistical method (two-way anova) was employed to select the genes significantly affected. An orderly pattern of gene responses was clearly detected, with genes being up- or down-regulated at specific timings consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma. IL-6 deficiency showed a dramatic effect in the expression of many genes, especially in the 1 day post-lesion timing, which presumably underlies the poor capacity of IL-6 knockout mice to cope with brain damage. The results highlight the importance of IL-6 controlling the response of the brain to injury as well as the suitability of microarrays for identifying specific targets worthy of further study.

Analysis of Variance↗

PubMed2005

Rates of divergence in gene expression profiles of primates, mice, and flies: stabilizing selection and variability among functional categories.

The extent to which natural selection shapes phenotypic variation has long been a matter of debate among those studying organic evolution. We studied the patterns of gene expression polymorphism and divergence in several datasets that ranged from comparisons between two very closely related laboratory strains of mice to comparisons across a considerably longer time scale, such as between humans and chimpanzees, two species of mice, and two species of Drosophila. The results were analyzed and interpreted in view of neutral models of phenotypic evolution. Our analyses used a number of metrics to show that most mRNA levels are evolutionary stable, changing little across the range of taxonomic distances compared. This implies that, overall, widespread stabilizing selection on transcription levels has prevented greater evolutionary changes in mRNA levels. Nevertheless, the range of rates of divergence is large with highly significant differences in the rate and patterns of transcription divergence across functional classes defined on the basis of the gene ontology annotation (primates and mice datasets) or on the basis of the pattern of sex-biased gene expression (Drosophila). Moreover, rates of divergence of sex-biased genes in the contrast between Drosophila species show a distinct pattern from that observed in the contrast between populations of D. melanogaster. Hence, we discuss the time scale of the changes observed and its consequences for the relationship between variation in gene expression within and between species. Finally, we argue that differences in mRNA levels of the magnitudes observed herein could be explained by a remarkably small number of generations of directional selection.

Animals↗

PubMed2004

Silencing of a gene adjacent to the breakpoint of a widespread Drosophila inversion by a transposon-induced antisense RNA.

Adaptive changes in nature occur by a variety of mechanisms, and Drosophila chromosomal inversions was one of the first studied examples. However, the precise genetic causes of the adaptive value of inversions remain uncertain. Here we investigate the impact of the widespread inversion 2j of Drosophila buzzatii on the expression of the CG13617 gene, whose coding region is located only 12 bp away from the inversion proximal breakpoint. This gene is transcribed into a 2.3-kb mRNA present in all D. buzzatii developmental stages. More importantly, the expression level of CG13617 is reduced 5-fold in embryos of lines homozygous for the 2j inversion compared with lines without the inversion. An antisense RNA that originates in the Foldback-like transposon Kepler inserted at the breakpoint junction in all of the 2j lines and that forms duplexes with the CG13617 mRNA in 2j embryos is most likely responsible for the near silencing of the gene. Few examples of RNA interference caused by transposable elements (TEs) have been previously described, but this mechanism might be prevalent in many organisms and illustrates the potential of TEs as a major source of genetic variation. In addition, because chromosomal rearrangements are usually induced by TEs, position effects might be more common than previously recognized and contribute significantly to the evolutionary success of inversions.

Animals↗

PubMed2004

Chromosomal rearrangements and the genomic distribution of gene-expression divergence in humans and chimpanzees.

The genomic DNA sequences of humans and chimpanzees differ by only 1.24%. Recently, however, substantial differences in gene-expression patterns between the two species have been revealed. In this article, we investigate the genomic distribution of such differences. Besides confirming previous findings about the evolution of sex chromosomes and duplications, we show that chromosomal rearrangements are associated with increased gene-expression differences in the brain and that rearrangements can have both direct and indirect effects on the expression of linked genes. In addition, our results are consistent with a role for some rearrangements in the original speciation events that separated the human and chimpanzee lineages.

Animals↗

PubMed2004

Human brain evolution: insights from microarrays.

Several recent microarray studies have compared gene-expression patterns n humans, chimpanzees and other non-human primates to identify evolutionary changes that contribute to the distinctive cognitive and behavioural characteristics of humans. These studies support the surprising conclusion that the evolution of the human brain involved an upregulation of gene expression relative to non-human primates, a finding that could be relevant to understanding human cerebral physiology and function. These results show how genetic and genomic methods can shed light on the basis of human neural and cognitive specializations, and have important implications for neuroscience, anthropology and medicine.

Animals↗

PubMed2003

Elevated gene expression levels distinguish human from non-human primate brains.

Little is known about how the human brain differs from that of our closest relatives. To investigate the genetic basis of human specializations in brain organization and cognition, we compared gene expression profiles for the cerebral cortex of humans, chimpanzees, and rhesus macaques by using several independent techniques. We identified 169 genes that exhibited expression differences between human and chimpanzee cortex, and 91 were ascribed to the human lineage by using macaques as an outgroup. Surprisingly, most differences between the brains of humans and non-human primates involved up-regulation, with approximately 90% of the genes being more highly expressed in humans. By contrast, in the comparison of human and chimpanzee heart and liver, the numbers of up- and down-regulated genes were nearly identical. Our results indicate that the human brain displays a distinctive pattern of gene expression relative to non-human primates, with higher expression levels for many genes belonging to a wide variety of functional classes. The increased expression of these genes could provide the basis for extensive modifications of cerebral physiology and function in humans and suggests that the human brain is characterized by elevated levels of neuronal activity.

Animals↗

PubMed2003

A new split of the Hox gene complex in Drosophila: relocation and evolution of the gene labial.

Hox genes encode transcription factors involved in the specification of segment identity in the early metazoan embryo. These genes are usually clustered and arranged in the same order as they are expressed along the anteroposterior body axis. This conserved genomic organization has suggested the existence of functional constraints acting on the genome organization. Partial disassembly of the Hox gene complex (HOM-C) in Caenorhabditis elegans and in two different Drosophila lineages, however, calls into question whether this cluster organization is absolutely required for proper function. Here we report a new split of the HOM-C discovered in the species of the Drosophila repleta group, which relocated the most anterior gene of the complex, lab, to a distant chromosomal site near the two most posterior Hox genes, abd-A and Abd-B. To investigate the evolutionary consequences of natural rearrangements of the Hox gene complex, the gene lab has been cloned and sequenced in D. buzzatii, a member of the D. repleta group with the split, and in D. virilis, a member of a different species group without the split. The results show that the structure of lab in D. buzzatii is intact and place the breakpoint at least 8 kb from its transcription start site. The nucleotide sequence evolution of lab in the genus Drosophila has been investigated by means of maximum likelihood methods. No significant variation has been observed among lineages in the rate of nucleotide substitution or in the nonsynonymous/synonymous substitution ratio. Seemingly, the relocation of lab has not induced a change in evolution rate or degree of functional constraint. Nevertheless, further work is needed to ascertain whether the lab-pb split has had any effects on gene expression.

Amino Acid Sequence↗

PubMed2003

The foldback-like transposon Galileo is involved in the generation of two different natural chromosomal inversions of Drosophila buzzatii.

Chromosomal inversions are the most common type of genome rearrangement in the genus Drosophila. Although the potential of transposable elements (TEs) for generating inversions has been repeatedly demonstrated in the laboratory, little is known on their role in the generation of natural inversions, which are those effectively contributing to the adaptation and/or evolution of species. We have cloned and sequenced the two breakpoints of the polymorphic inversion 2q7 of D. buzzatii. The sequence analysis of the breakpoint regions revealed the presence in the inverted chromosomes of large insertions, formed by complex assemblies of transposons, that are absent from the chromosomes without the inversion. Among the transposons inserted, the Foldback-like element Galileo, that was previously found responsible of the generation of the widespread inversion 2j of D. buzzatii, is present at both 2q7 breakpoints and is the most likely inducer of the inversion. A detailed study of the nucleotide and structural variation in the breakpoint regions of six chromosomal lines with the 2q7 inversion detected no nucleotide differences between them, which suggests a monophyletic and recent origin. In contrast, a remarkable degree of structural variation was observed in the same six chromosomal lines. It thus appears that the two breakpoints of the inverted chromosomes have become genetically unstable hotspots, as was previously found for the 2j inversion breakpoints. The possibility that this instability is caused by structural properties of Foldback elements is discussed.

Animals↗

PubMedDate not supplied

Localization of parathyroid adenomas by (99m)Tc-sestamibi scanning: upper neck versus lower neck lesions.

OBJECTIVE: To assess the diagnostic properties of (99m)Tc-sestamibi scanning (dual-phase technique) in patients with primary hyperparathyroidism and to establish the overall efficacy of this imaging technique for localization of an adenoma. METHODS: The medical records of all 131 patients who underwent parathyroid scanning in a tertiary care center between January 1997 and December 2002 were reviewed. The surgical findings were used as the "gold standard" for the diagnosis of parathyroid pathologic conditions. RESULTS: Primary hyperparathyroidism was diagnosed in 87 of the 131 patients (66.4%); of these, 76 underwent surgical treatment. In 44 patients, sestamibi scanning was also done for conditions other than primary hyperparathyroidism. (99m)Tc-sestamibi scanning had a sensitivity of 79.1%, a specificity of 86.7%, a positive predictive value of 88.3%, a false-positive rate of 11.6%, and a false-negative rate of 23.3% for the diagnosis of parathyroid adenoma. Despite the apparent high sensitivity of this scanning technique, only 58.2% of the adenomas were found intra-operatively at the location predicted by the scan. Lesions in the upper neck area were missed more frequently by sestamibi scanning than were those in the lower neck area (13 of 32 versus 1 of 35, respectively) (P<0.05). CONCLUSION: Preoperative localization of parathyroid adenomas with use of (99m)Tc-sestamibi scanning showed a limited capacity to reveal their precise location. Thus, such scans must be complemented with other studies, such as intraoperative ultrasonography and rapid parathyroid hormone assay, to ensure a successful excision if a limited surgical procedure is planned.

Adenoma↗