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Biomedical subjects

Juan Bernal

Publications and source records attributed to Juan Bernal.

At least 19 recordsLinked to original sources
PubMed2006

Analysis of Rhes activation state and effector function.

Rhes/RASD2 is a novel Ras homolog with almost restricted expression in the brain and highly enriched in the striatum, where it is controlled by thyroid hormone during the postnatal period. Little is known about its biochemical properties and cell signaling function, but the data available so far indicate that Rhes is constitutively bound to GTP and activates PI3K, and, on the other hand, interferes with cAMP/PKA pathway activation induced by G protein-coupled receptors.

Animals↗
PubMed2006

Generation and characterization of dickkopf3 mutant mice.

dickkopf (dkk) genes encode a small family of secreted Wnt antagonists, except for dkk3, which is divergent and whose function is poorly understood. Here, we describe the generation and characterization of dkk3 mutant mice. dkk3-deficient mice are viable and fertile. Phenotypic analysis shows no major alterations in organ morphology, physiology, and most clinical chemistry parameters. Since Dkk3 was proposed to function as thyroid hormone binding protein, we have analyzed deiodinase activities, as well as thyroid hormone levels. Mutant mice are euthyroid, and the data do not support a relationship of dkk3 with thyroid hormone metabolism. Altered phenotypes in dkk3 mutant mice were observed in the frequency of NK cells, immunoglobulin M, hemoglobin, and hematocrit levels, as well as lung ventilation. Furthermore, dkk3-deficient mice display hyperactivity.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Role of the renin-angiotensin-aldosterone system in diastolic heart failure: potential for pharmacologic intervention.

Congestive heart failure (CHF) is a major public health problem that results in tremendous economic burden. Diastolic heart failure (DHF) forms an important subset with increasing incidence and prevalence. There are widely variable estimates of the prevalence, ranging from 13% to 74% of all CHF presentations, and this is predominantly a result of a lack of uniform criteria for establishing a diagnosis. New developments in management of DHF have lagged behind those for systolic heart failure (SHF), for which numerous new therapeutic and device strategies have been instituted. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of both SHF as well as DHF. The beneficial role of ACE inhibitors as well as aldosterone antagonists in SHF has been well established. Because of its unique role of the RAAS in establishing fibrosis at a molecular level, RAAS blockade provides an opportunity to expand the therapeutic options for DHF. Thus far, in patients with primary DHF only the angiotensin receptor type 1 antagonist candesartan has been reported to decrease morbidity and probably mortality. Large, ongoing randomized trials including TOPCAT (Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart) and the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) are currently underway to establish the role of aldosterone antagonists in patients with DHF.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

RC3/neurogranin is expressed in pyramidal neurons of motor and somatosensory cortex in normal and denervated monkeys.

RC3/neurogranin is a neuron-specific calpacitin located in the cytoplasm and, especially, in dendrites and dendritic spines of cortical neurons, involved in many aspects of excitatory transmission and long-term potentiation. We investigated RC3 expression in pyramidal cortical neurons and interneurons of the motor and somatosensory cortex of normal Macaca fascicularis by means of double immunofluorescence and with techniques that combine immunohistochemistry and radioactive in situ hybridization. We show that RC3 is expressed in virtually all pyramidal neurons and spiny stellate neurons of neocortical areas 4, 3b, 1, 2, 5, 7, and SII, but not in the majority of cortical interneurons. RC3 protein and mRNA are tightly colocalized with the alpha subunit of CaM kinase II and the 200-kD, nonphosphorylated neurofilament, whereas they are absent from cells expressing the 27-kD, vitamin D-dependent calbindin and parvalbumin. In order to investigate possible activity-dependent regulation of the expression of RC3, we compared these results with those obtained from monkeys subjected to chronic peripheral cutaneous denervation of the first finger. We found that the pattern of distribution of RC3 in motor and somatosensory cortices after nerve cut did not differ from normal.

Afferent Pathways↗
PubMed2005

Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment.

The transcriptional properties of unliganded thyroid hormone receptors are thought to cause the misdevelopment during hypothyroidism of several functions essential for adult life. To specifically determine the role of unliganded thyroid hormone receptor alpha1 (TRalpha1) in neuronal tissues, we introduced a mutation into the mouse TRalpha1 gene that lowers affinity to thyroid hormone (TH) 10-fold. The resulting heterozygous mice exhibit several distinct neurological abnormalities: extreme anxiety, reduced recognition memory, and locomotor dysfunction. The anxiety and memory deficiencies were relieved by treatment with high levels of TH in adulthood, an effect that correlated with a normalization of GABAergic inhibitory interneurons in the hippocampal CA1 region. In contrast, a post-natal TH treatment was necessary and sufficient for ameliorating the adult locomotor dysfunction. Here, the hormone treatment normalized the otherwise delayed cerebellar development. The data thus identify two novel and distinct functions of an unliganded TRalpha1 during development and adulthood, respectively.

Animals↗
PubMed2005

Thyroid hormones and brain development.

The action of thyroid hormones (thyroxine, T4; triiodothyronine, T3) on brain development and function is gaining renewed interest. It has been known for many years that thyroid hormones are very important in mammalian brain maturation, influencing many aspects related to neural cell migration, differentiation, and signaling. In the last 10 years, genes regulated by thyroid hormones have been identified in the rodent brain, and understanding of the role of thyroid hormone nuclear receptors has been facilitated with the analysis of the phenotype of mutant mice for the different receptor isoforms. The general picture that emerges is that T4 and T3 may enter the brain through specific transporters. T4 is converted to the active hormone, T3, in glial cells, astrocytes, and tanycytes, although the main target cells are neurons and maturing oligodendrocytes. T3, acting through the nuclear receptors, controls the expression of genes involved in myelination, cell differentiation, migration, and signaling. In addition to transducing the T3 signal, the nuclear receptors also have activity in the unliganded state (i.e., as aporeceptors), mainly as repressors of transcription. The physiological meaning of aporreceptor action is not known, but they may play a role in the genesis of the hypothyroid phenotype. Among the questions that remain to be explored in more detail is the role of thyroid hormones and the T3 receptors, both liganded and unliganded, in the fetal brain, especially before onset of fetal thyroid gland function. These questions are relevant for human health and the management of thyroid diseases during pregnancy.

Animals↗
PubMed2004

The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors.

The Ras homolog enriched in striatum, Rhes, is the product of a thyroid hormone-regulated gene during brain development. Rhes and the dexamethasone-induced Dexras1 define a novel distinct subfamily of proteins within the Ras family, characterized by an extended variable domain in the carboxyl terminal region. We have carried this study because there is a complete lack of knowledge on Rhes signaling. We show that in PC12 cells, Rhes is targeted to the plasma membrane by farnesylation. We demonstrate that about 30% of the native Rhes protein is bound to GTP and this proportion is unaltered by typical Ras family nucleotide exchange factors. However, Rhes is not transforming in murine fibroblasts. We have also examined the role of Rhes in cell signaling. Rhes does not stimulate the ERK pathway. By contrast, it binds to and activates PI3K. On the other hand, we demonstrate that Rhes impairs the activation of the cAMP/PKA pathway by thyroid-stimulating hormone, and by an activated beta2 adrenergic receptor by a mechanism that suggests uncoupling of the receptor to its cognate heterotrimeric complex. Overall, our results provide the initial insights into the role in signal transduction of this novel Ras family member.

Animals↗
PubMed2004

Rhes is involved in striatal function.

The development and the function of central nervous system depend on thyroid hormones. In humans, the lack of thyroid hormones causes cretinism, a syndrome of severe mental deficiency. It is assumed that thyroid hormones affect the normal development and function of the brain by activating or suppressing target gene expression because several genes expressed in the brain have been shown to be under thyroid hormone control. Among these, the Rhes gene, encoding a small GTP-binding protein, is predominantly expressed in the striatal region of the brain. To clarify the role of Rhes in vivo, we disrupted the Rhes gene by homologous recombination in embryonic stem cells and generated mice homozygous for the Rhes null mutation (Rhes(-/-)). Rhes(-/-) mice were viable but weighed less than wild-type mice. Furthermore, they showed behavioral abnormalities, displaying a gender-dependent increase in anxiety levels and a clear motor coordination deficit but no learning or memory impairment. These results suggest that Rhes disruption affects selected behavioral competencies.

Age Factors↗
PubMed2003

Aberrant maturation of astrocytes in thyroid hormone receptor alpha 1 knockout mice reveals an interplay between thyroid hormone receptor isoforms.

Although the effects of thyroid hormones on the development of neurons and oligodendrocytes are well documented, less is known about the hormonal effects on astrocytes. Our analyses of cerebellar slices from 2-month-old T(3) receptor protein (TR)alpha1-deficient mice show that mature astrocytes, Golgi epithelial cells, and their Bergmann processes had strongly reduced glial fibrillary acidic protein (GFAP) and nestin immunoreactivity, in contrast to wild-type mice. Furthermore, the Bergmann processes exhibited an irregular GFAP staining. A similar expression of nestin and GFAP was observed in 11-d-old (P11) mutant pups. Surprisingly, however, hypothyroidism normalized the appearance of these markers in the P11 mutants, suggesting that liganded TR beta is detrimental to astroglial cell differentiation in the absence of TR alpha 1. To test this hypothesis, hypothyroid mice were treated from birth until P11 with the TR beta-selective ligand GC-1. This treatment was devastating in the TR alpha 1(-/-) mice, causing little if any nestin or GFAP immunoreactivity, whereas the wild-type mice were normal. The results thus indicate an important interplay between thyroid hormone receptor isoforms in astroglial cell maturation.

Animals↗
PubMed2003

Differential effects of triiodothyronine and the thyroid hormone receptor beta-specific agonist GC-1 on thyroid hormone target genes in the b ain.

The availability of synthetic thyroid hormone receptor agonists provides a valuable tool to analyze whether specific receptor isoforms mediate specific physiological responses to thyroid hormone. GC-1 is a thyroid hormone analog displaying selectivity for thyroid hormone receptor beta. We have analyzed the effect of GC-1 on expression of thyroid hormone target genes in the cerebrum and cerebellum. Congenitally hypothyroid rats were treated with single daily doses of either T3 or GC-1. Both compounds similarly induced Purkinje cell protein-2 (PCP-2) in the cerebellum. Expression of RC3 and Rhes in the caudate, and hairless, neurotrophin-3, Reelin, and Rev-ErbAalpha in the cerebellum, was analyzed by in situ hybridization on postnatal d 16. Hypothyroidism strongly decreased expression of RC3 and Rhes in the caudate, and hairless, Rev-ErbAalpha, and neurotrophin-3 in the cerebellum, and increased Reelin. T3 treatment normalized the expression of all genes. However, GC-1 effectively normalized expression of Rhes and Reelin only. The lack of a GC-1 effect on most cerebellar genes can be explained by the known distribution of thyroid hormone receptor alpha and beta isoforms. However, in the caudate, RC3 and Rhes are expressed in the same cells, and therefore, they may represent specific gene responses linked to specific thyroid hormone receptor isoforms.

Acetates↗
PubMed2003

Alien/CSN2 gene expression is regulated by thyroid hormone in rat brain.

Alien has been described as a corepressor for the thyroid hormone receptor (TR). Corepressors are coregulators that mediate gene silencing of DNA-bound transcriptional repressors. We describe here that Alien gene expression in vivo is regulated by thyroid hormone both in the rat brain and in cultured cells. In situ hybridization revealed that Alien is widely expressed in the mouse embryo and also throughout the rat brain. Hypothyroid animals exhibit lower expression of both Alien mRNAs and protein levels as compared with normal animals. Accordingly, we show that Alien gene is inducible after thyroid hormone treatment both in vivo and in cell culture. In cultured cells, the hormonal induction is mediated by either TRalpha or TRbeta, while cells lacking detectable amounts of functional TR lack hormonal induction of Alien. We have detected two Alien-specific mRNAs by Northern experiments and two Alien-specific proteins in vivo and in cell lines by Western analysis, one of the two forms representing the CSN2 subunit of the COP9 signalosome. Interestingly, both Alien mRNAs and both detected proteins are regulated by thyroid hormone in vivo and in cell lines. Furthermore, we provide evidence for the existence of at least two Alien genes in rodents. Taken together, we conclude that Alien gene expression is under control of TR and thyroid hormone. This suggests a negative feedback mechanism between TR and its own corepressor. Thus, the reduction of corepressor levels may represent a control mechanism of TR-mediated gene silencing.

Animals↗
PubMed2003

Perspectives in the study of thyroid hormone action on brain development and function.

The purpose of this review is to provide an up-to-date report on the molecular and physiologic processes involved in the role of thyroid hormone as an epigenetic factor in brain maturation. We summarize the available data on the control of brain gene expression by thyroid hormone, the correlation between gene expression and physiologic effects, and the likely mechanisms of action of thyroid hormone on brain gene expression. In addition we propose a role for unliganded thyroid hormone receptors in the pathogenesis of hypothyroidism. Finally, we review recent data indicating that thyroid hormone receptors have an impact on behavior.

Animals↗
PubMed2003

Divergent expression of type 2 deiodinase and the putative thyroxine-binding protein p29, in rat brain, suggests that they are functionally unrelated proteins.

Deiodinases (D1, D2, and D3) are selenoproteins involved in thyroid hormone metabolism. Generation of the active hormone T(3), from T(4), is carried out by D1 and D2, whereas D3 degrades both hormones. The identity of the cloned D2 as a selenoprotein is well supported by biochemical and physiological data. However, an alternative view has proposed that type 2 deiodinase is a nonselenoprotein complex containing a putative T(4) binding subunit called p29, with an almost identity in sequence with the Dickkopf protein Dkk3. To explore a possible functional relationship between p29 and D2, we have compared their mRNA expression patterns in the rat brain. In brain, parenchyma p29 was expressed in neurons. High expression levels were found in all the regions of the blood-cerebrospinal fluid (CSF) barrier. p29 was present in different types of cells than D2, with the exception of the tanycytes. Our data do not support that p29 has a functional relationship with D2. On the other hand, expression of p29 in the blood-CSF barrier suggests that it might be involved in T(4) transport to and from the CSF, but further studies are needed to substantiate this hypothesis.

Animals↗
PubMed2002

Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism.

Thyroid hormone (T3) controls critical aspects of cerebellar development, such as migration of postmitotic granule cells and terminal differentiation of Purkinje cells. T3 acts through nuclear receptors (TR) of two types, TRalpha1 and TRbeta, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TRalpha1 isoform, which normally accounts for about 80% of T3 receptors in the cerebellum. Contrary to what was expected, granule cell migration and Purkinje cell differentiation were normal in the mutant mice. Even more striking was the fact that when neonatal hypothyroidism was induced, no alterations in cerebellar structure were observed in the mutant mice, whereas the wild-type mice showed delayed granule cell migration and arrested Purkinje cell growth. The results support the idea that repression by the TRalpha1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TRbeta-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TRalpha1 and TRbeta, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TRbeta but not TRalpha1, partially corrects Purkinje cell differentiation but has no effect on granule cell migration. Our data indicate that thyroid hormone has a permissive effect on cerebellar granule cell migration through derepression by the TRalpha1 isoform.

Animals↗