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Expresion diferencial global de genes localizados en la Region Critica del Sindrome de Down en el cerebro humano normal.

Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain

Introduction

The brain is the system responsible for a wide variety of biological processes ranging from simple motor functions to complex cognitive processes. Among all anatomical areas that comprise the brain, it is possible to highlight the basal nuclei and the structures that are part of the limbic system, highly related to motor functions as well as in learning and memory processes (1).

The cerebral homeostasis is measured by complex interactions that must be carried out between the great abundance and diversity of neurons, glial cells and non-neuronal cells that comprise it. This derives from an accurate gene regulation in all structures (2). It has been observed that approximately 30% of all human genes express mainly in this organ. Besides, that cerebral level of transcription have a marked variability that depends on the analyzed area, associated to groups of genes co-expressing mainly in certain brain areas (3). However, most studies have been conducted on homogenate tissues, having to discern about the cellular heterogeneity and the functionality of such genes in those regions.

The abnormal variation in gene dosage can lead to a number of disorders that produce, among other things, neurological class dysfunctions. Thus, Down syndrome (DS) is caused by partial or total triplication of the genes found on chromosome 2', being the most frequent aneuploid which produces varying degrees of cognitive disability (4,5). Studies on partial trisomies have allowed the characterization of a region of the chromosome 2' known as Down Syndrome Critical Region (DSCR). It is located at the distal end of the long arm of chromosome 21 (21q22.1-22.3), and has candidate genes whose imbalance may induce a marked cognitive deficit, as well as other pathologies and associated conditions (6).

Although the involvement of DSCR as the sole cause of DS symptomatology is still a topic of debate, different studies have suggested that this region plays a primary role in the genetic interactions that could be related to the pathogenesis of DS7. However, the subset of genes that are over expressed on chromosome 21 and generate these deficiencies, are not completely known (8); moreover, some of them do not over express in the trisomic fetal brain (9). For this reason, a detailed knowledge of the expression DSCR genes in normal human brains, could provide a greater understanding of their participation on the cognitive processes while, at the same time, more will be known about their implications in both, neurological dysfunctions associated with DS as in other neuropathologies such as Alzheimer disease.

Some methodologies have been implemented to study the cerebral transcriptome. One of them is the DNA microarrays that allow the analysis of many tissues by measuring the gene expression. In this way, some comparative studies among expression profiles of different brain zones have been accomplished in order to better understand, the physiopathology of many diseases (10,11). However, in this sense, there are several constraints, ranging from the collection of a significant number of brains from donors with no neuropsychiatric and/or neuropathology history, to the correct extraction of brain tissue and optimum quality of RNA in all structures.

In this scenario, bioinformatics databases allowed to extract complete and detailed information of the levels of gene transcription from several brain structures obtained from rigorous computational tools as well as from experiments using microarrays of DNA of postmortem human brains.

The Allen Institute of Brain Science has compiled a public database called Allen Human Brain Atlas (http://www.alleninstitute.org) that includes anatomic measurements of gene expression and genomic information of human brains. It also has a set of visualization tools and data mining including a complete coverage from histological preparations and microarray data with more than 62,000 probes being possible to obtain transcriptional data of thousands of genes referentiated with Entrez Gene Encode. At least two different probes are available for 93% of 21,245 from the genes consigned. We designed a bioinformatics model of the expression profiles of 19 genes located at DSCR in 24 specific substructures of cerebral nuclei and 18 from the limbic lobe of normal human brain. Data of brain gene expression coming from DNA microarray experiments are available at the free access database of the human brain project of the Brain Atlas of "Allen Institute for Brain Sciences" in Seattle, Washington (http://www.brain-map.org). The results conducted us to approach to a systemic model of expression that can be bioinformatically modified to extrapolate it with other brain pathologies, thus providing a powerful tool for its understanding.

Materials and Methods

Type of study

This descriptive bioinformatics study (in silico), used the Allen Human Brain Atlas free online database (http://human.brain-map.org), which is supported by the Allen Institute for Brain Sciences. The expression level of 19 DSCR genes (21q22.12-22.2) was studied in the cerebral nuclei and the limbic lobe.

Data mining

With the help of the graphic cursor from the electronic page of the human brain project from the Allen Institute for Brain Sciences, the gene expression level values, along the different substructures of the limbic lobe and the cerebral nuclei, were identified and registered as well as the standard data (z-score). These values were entered into electronic Excel sheets for further analysis. For each one of the substructures included in the study, three values were taken at three different points of each brain substructures considering as data the correspondent z-score mean. The z-score had normalized value in ranges from -3 to +3. Additionally, genomic information was extracted from Gene Ontology application (GO) (http://www.geneontology.org/index.shtml). The cellular location, the molecular function and the biologic process of the selected genes were itemized.

Calculating the Z-score

We consider appropriate to describe in a general way the experimental procedures that led us to obtain the registered z-score data. The procedures are reported extensively on the technical report of The Allen Institute of Brain Science.

The z-score values were calculated by subtracting the total average intensity of the genes in the microarray from the intensity of each individual gene within a single experiment and dividing the result by the standard deviation (SD) of the measure of all the intensities in accordance with the following formula: Z score= (G intensity - average intensity of G1 ... Gn)/DSG1 ... Gn. Where G is a gene within the microarray and G1 ... Gn represents the aggregate measure of all genes in the microarray (12).

Selection of genes and brain structures

The main inclusion criteria that was followed to select the nineteen genes included in this study was the linkage of the gene product with clinical manifestations of Down syndrome (Table 1). Structures of the cerebral nuclei and the limbic lobe were chosen because they showed higher expression in a preliminary study performed with eight genes of DSCR (13). The main information of each one of the nineteen genes is described in table 2.

Statistical analysis

Statistical analyses were performed using STATGRAPHICS Centurion XVI (http://www.statgraphics.com) and Systat 13 programs (http://www.systat.com). The differences between the data were calculated using a multiple comparison analysis estimating its significance with the Mann and Whitney test for multiple comparisons. Differences in expression levels per gene and anatomical area were modeled through the scatter plot using as comparison measure the Pearson partial correlation values with a significance of 95% (p <0.05). The multiple regression analysis of paired comparisons was carried out using the Bayesian regression calculation. To rank the expression in several brain substructures of cerebral nuclei and limbic lobe for each one of genes a Principal Components Analysis (PCA) was performed reducing the R space from 19 coliner variables to 6 principal components ([R.sup.19] > [R.sup.6]); the PCA analysis was complemented with a Cluster Analysis (CA).

Results

Differential expression of DSCR in human brain A quantitative analysis of global transcription of DSCR genes along the structures of the brain nuclei and the limbic lobe revealed that the highest values of z-score were registered in the area that includes the putamen for DSCR3, RCAN1 as well as in left and right caudate nuclei for DSCR6, and the left and right globus pallidus for DSCR3, SH3GBR, DYRK1A, CLIC6 and PRMT2. Moreover, in the limbic lobe, the highest expression values were registered at DG for DYRK1A and KCNJ6 and in the CA1 and CA2 for DSCR3 and KCNJ6 (Fig. 1A). In contrast, the lowest values of expression were registered in basal caudate nuclei for KCNJ6, PSMG1; in CA3, and CA4 for PIGP, DSCR6 and PRMT2 (Fig. 1B).

Expression in cerebral nuclei

The RCAN1 gene showed high levels of expression in the left putamen (z-score 2.87), the PUr (2.66) and in the left external globus pallidus (2.67); whereas in the C-l, it was registered a lowest level of expression (-1.268). The DSCR2 was not over-expressed in any of the structures of this brain area; however, it is important to highlight that from the all structures of cerebral nuclei, the Pu-l, the Pu-r and the GPE-l, were the areas with lower transcription levels. The DSCR3 showed low expression overall the structures, however, in the GPE-l the highest value of z-score was registered (1.089) in contrast with the ABL-l where a low level of expression was recorded (-1.28).

DSCR4 registered a high z-score in nucleus accumbens -NA- (1.84) and in Pu-r (1.40). In the nucleus of the left amygdala, the z-score was -1,022. PIGP had the highest expression in the Pu-r (1.97). DSCR6 was variable levels of expression in the different structures of cerebral nuclei. However, the highest z-score values were for the Pu-l (2.95); in CNH-l (2.04); CNH-r (2.31) and CNT-r (2.62). The highest-score of DSCR8 (1.46) was observed in the Pu-l. DSCR10 had high levels of expression in CN-r (2.58) and in GPE-r (2.16), whereas ATZ had the lowest z-score (-1.72).

BACE2 and ERG showed a maximum level of expression in the external and internal left globus pallidus (2.44/2.09 and 2.37/2.22) respectively. BACE2 also had over-expression in the GPI-r (2.176). DSCAM, DYRK1A, KCNJ6 had low expression levels in the caudate nucleus (-1.94/-1.86/-2.28). DYRK1A and KCNJ6 also presented under expression in GPE-r (-1.69/-1.57). Additionally, KCNJ6 registered low expression in the left (-2.40) and right (-2.16) putamen and left internal and external globus pallidus (-1.78/-1.53). RUNX1 and SIM2 presented maximum under expression in the nucleus of the amygdale (-1.93/-1.62). Moreover, RUNX1 registered mid values of over expression in CN, Pu and GP; BRWD1, CLIC6, ETS2, and SH3BGR had low levels of expression.

Expression in the limbic lobe

In CA4-l the highest values of z-score for DSCR1, 2, 3, 4, 5, 6 y 8 were recorded (2.04 [+ or -] 0.56). In other structures, variable levels of expression were observed being DSCR1 the one with the lowest level of expression. PIGP showed its highest level of expression in CA4-r (2.09). In the subiculum, DSCR6 recorded a low level of expression (-1.39). CLIC6 had high values of expression in CA1-l (2.807) and in PHG-r (2.147). BRWD1 and DYRK1A registered low levels of expression in the CA 4 (-1.598/-1.506 respectively). BACE2 and RUNX1 showed variable low levels of expression in left dental gyrus (-2.431/-1.355) respectively. On the other hand, ERG, ETS2, SH3BGR, SIM2 had in general low, levels of expression.

Co-expression of genes located in DSCR along the different regions of the normal human brain

A Cluster Analysis (CA), using the median distance values, revealed that the expression of some genes was produced in association with a series of sub structures both from cerebral nuclei and limbic lobe (Fig. 2). For CA3 and DG, a high association in the co-expression of the genes DSCR2, KCNJ6 was determined. In contrast, in the CN and the GP, a high association in the co-expression of RUNX-1, ERG y SIM2 was recorded. In CN, it was possible to define a close association in the co-expression of DSCR1, DSCR6, DCR10 and CLIC-6.

The PCA for the cerebral nuclei showed six components that included 85.6% of the total variance. In the first component, DSCR1, 8, 10, BACE2, ERG and RUNK1 genes were grouped, while in the second component DSCR4 and ETS2 genes were included. For the Limbic Lobe, six components were discriminated that explained 76.1% of the total variance. The first component DSCR1, ERG y RUNK1 genes were grouped; in contrast with the second component in which DSCR4, DSCR 8 and ETS2 were grouped.

The biplots showed two associations for the cerebral nuclei: The first one included the genes DSCAM, DSCR4, DSCR8 and SIM2; while the second included ERG and RUNX (Fig. 3 right). On the other hand, for the limbic lobe the analysis also showed two associations in which the first one included DSCR2, 5 and 6 whereas the second one grouped DSCAM and DSCR4 (Fig. 3 left).

Discussion

One of the mid-term effects of the Human Genome Project is the large volume of data recorded in different databases making possible its bioinformatics use. The results of these analyses have prompted a new way to understand biological phenomena in silico by using different genomic variables recorded in on line databases. In this sense, this study allowed to develop a topographic map of the expression of 19 DSCR genes along different structures of normal human brain. The results obtained evidenced that the transcription of DSCR genes was differential, besides being dependent of the brain-associated structure. Thus, it can be concluded that in a normal brain, the nineteen DSCR genes analyzed, are expressing themselves differentially under a highly precise regulation of its transcription, being this dependent on the functional process of every structural components of human brain.

Previous reports have shown high levels of expression of RCAN1 in cortex, midbrain and cerebellum of mouse DS model (14), and of PIGP gene in the developing brain (15). Moreover, the PIG-P, a gene encoding a component of glicosil fosfatidilinositol-N-acetilglucosaminil transferase (GPI-GnT), was twice over expressed in cerebral cortex, in contrast with DSCR6 whose expression was normal. DSCR4 was not detected in fetal brain (16). Although those previous results evidenced a structure specific differential trancription, our results showed in a more detailed way how the transcription of DSCR genes is particular to each of them and has transcriptional profiles that are dependent upon the brain substructure involved.

Our results showed that RCAN1 and RUNX1 were over expressed in important brain structures associated with several function of learning and cognition, in contrast with DYRK1A that was under expressed in the same brain substructures. Previous results have shown that RUNX1 protein is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. Its transcription unit located in chr21: 35, 086, 302-35, 343, 066, has a size of 261,498 bp and contains 9 exons; possibly to be involved in the development of normal hematopoiesis (17). Moreover chromosomal translocations involving this gene are well documented and have been associated with several types of leukemia (18).

The protein encoded by RCAN1, which its transcription unit is located at chr21: 34, 812, 252-34, 909, 180 having a size of 96,929 bp and containing 4 exons, interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways, possibly affecting central nervous system development (19). RCAN1 gene is located in the minimal candidate region for the Down syndrome phenotype, and is overexpressed in the brain of Down syndrome fetuses. Chronic overexpression of RCAN1 may lead to neurofibrillary tangles such as those associated with Alzheimer disease (20).

On the other hand, DYRKA1 which transcription unit is located at chr21: 37, 714, 547-37, 806, 704 has a size of 92,158 bp and contains 11 exons, encoding a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. DYRKA1 contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeats that catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. It is considered to be a strong candidate gene for learning defects associated with Down syndrome (21).

Moreover, DYRK1A phosphorylates several transcriptional factors, such as CREB and NFAT, endocytic complex proteins, and AD-linked gene products, RCAN1 is an endogenous inhibitor of calcineurin A, and its unbalanced activity is thought to cause major neuronal and/or non-neuronal malfunction in Down syndrome and Alzheimer disease. Interestingly, DYRK1A and RCAN1 contribute to the learning and memory deficit, altered synaptic plasticity, impaired cell cycle regulation, and Alzheimer Disease-like neuropathology in DS. Such results could suggest a potential feedback as an important mechanism of transcription control in these brain areas (22).

A remarkable feature of the present study was the identification of a differential transcriptional control via negative feedback of several genes that depend upon specific brain substructures. One example of it was the overexpression of RCAN1, RUNX1 in contrast with the underexpression of DYRK1A that occur in caudate nuclei head left and right, putamen, internal and external globus pallidus of normal brain Such result, lead us to propose that in normal brain, expression of these genes in specific structures of cerebral nuclei, and limbic lobe regulate not only cognitive function but emotional ones via a complex network of gene expression responsible by the learning and memory functions among others associated process (23,24). Previously it was reported that DYRK1A overexpression and numerous cytosolic, cytoskeletal and nuclear proteins, including transcription factors, are phosphorylated by DYRK1A. Contrasting with underexpression in normal brain described in the present study, DYRK1A overexpression is a central point for the deregulation of multiple pathways in the developing and aging DS brain, with structural and functional alterations including mental retardation and dementia. Moreover, the enhanced phosphorylation of amyloid precursor protein by overexpressed DYRK1A facilitates amyloidogenic amyloid precursor protein cleavage elevating A[beta]40 leading to brain [beta]-amyloidosis observed in Alzheimer disease (25).

The putamen is the portion of the basal nuclei that form the most external part of the lenticular nucleus and seems to play an important role in the operative conditioning (learning through reinforcement) (26). The somatosensory and motor cortices, the intralaminar nucleus of the thalamus and the substantianigra, project to the putamen and this, in turn, projects in motor and promotor areas of the cortex through the globus pallidus and the thalamus (27). In addition, the caudate nucleus is one of the components of the basal ganglia located next to the cerebellum, participating indirectly in movement modulation from the cortex to the nuclei and from these back to the motor cortex via thalamic nuclei. It has been shown that the caudate nucleus is heavily involved in learning and memory particularly in the treatment of feedback . Moreover, the limbic lobe contains the circunvolution of callous body, the subcallous circunvolution and the parahypocampal gyrus, being apparently the main responsable of emotional life, influencing the formation of memories, in association with the hyoptalamus, hypocampus, amigdala and other four brain areas. Overall the results obtained in the present study, lead us to postulate the existence of a correlation between high transcription levels of some DSCR genes in these structures and their potential role in the associated cognitive and emotional functions (28, 29).

Previous reports showed that Calcineurin-nuclear factor of activated T cells (NFAT) signalling plays a critical role not only in the immune and nervous systems, but also in cardiovascular development and pathological endothelial cell activation during angiogenesis or inflammation (30). The 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down's sindrome. A mathematical modelling have predicted that autoregulation within of the pathway DSCR1, DYRK1A and NFATc accentuates the effects of trisomy, leading to failure to activate target genes under specific conditions (31).

The brain homeostasis is measured by complex gene interactions that must be carried out between the great abundance and diversity of cells, which ultimately derives from the precise gene regulation in all structures. The results obtained in this study not only confirm it but extended the concept about designing a systemic model of global gene expression of nineteen genes located in the Down syndrome critical region in important structures of normal human brain that are controlling process of learning, movement and emotions.

Article history

Received: 2 July 2014

Revised: 10 November 2014

Accepted: 19 December 2014

Acknowledgments

We thank Universidad del Valle and Universidad Autonoma de Occidente for their financial support and for the infrastructure to conduct this research.

Conflict of interest. None of the authors has conflicts of interest related to this study.

References

(1.) Critchley HD, Harrison NA. Visceral influences on brain and behavior. Neuron. 2013; 77: 624-638.

(2.) Johnson M, Kawasawa M, Mason C, Krsnik Z, Coppola G, et al. Bogdanovic' D Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron. 2009; 62: 494-509.

(3.) Oldham M, Konopka G, Iwamoto K, Langfelder P, Kato T, Horvath S, et al. Functional organization of the transcriptome in human brain. Nat Neurosci. 2008; 11: 1271-1282.

(4.) Nieuwenhuis-Mark R Diagnosing Alzheimer's dementia in Down syndrome: Problems and possible solutions. Res Dev Disabil. 2009; 30: 827-838.

(5.) Abbeduto L, McDuffie A. Genetic Syndromes Associated with Intellectual Disabilities. In: Handbook of Medical Neuropsychology: Applications of Cognitive Neuroscience. Armstrong, CL, Morrow L (Eds) New York: Springer; 2010. pp. 193-221.

(6.) Korenberg Julie R, Kawashima Hiroko, Pulst Stefan-M, Ikeuchi T, Ogasawara N, Yamamoto K, et al. Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Human Genet. 1990; 47: 236-46.

(7.) Montoya J, Soto J, Satizabal J, Sanchez A, Garcia Vallejo F. Genomic study of the critical region of chromosome 21 associated to Down syndrome. Colomb Med (Cali). 2011; 42: 26-38.

(8.) Weitzdoerfer R, Dierssen M, Fountoulakis M, Lubec G. Fetal life in Down syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure. J Neural Transm Suppl. 2001; 61: 59-70.

(9.) Ferrando-Miguel R, Cheon M, Lubec G. Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain (Part V): Overexpression of phosphatidyl-inositol-glycan class P protein (DSCR5) Amino Acids. 2004; 26: 255-61.

(10.) VanGilder R, Huber J, Rosen C, Barr T. The transcriptome of cerebral ischemia. Brain Res Bull. 2012; 88: 313-9.

(11.) Zeng H, Shen E, Hohmann J, Oh S, Bernard A, Royall J, et al. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures. Cell. 2012; 149: 483-96.

(12.) Cheadle C, Cho-Chung YS, Becker KG, Vawter MP Application of z-score transformation to Affymetrix data. Appl Bioinformatics. 2003; 2: 209-17.

(13.) Montoya J, Pena A, Satizabal J, Garcia-Vallejo F. In silico systemic analysis of the differential expression of genes located in criticalregion of Down syndrome in the human brain. Rev Med. 2012; 20: 15-26.

(14.) Amano K, Sago H, Uchikawa C, Suzuki T, Kotliarova SE, Nukina N, Epstein CJ, Yamakawa K. Dosage-dependent overexpression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome. Hum Mol Genet. 2004; 13: 1333-40.

(15.) Shao M, Liu ZZ, Wang CD, Li HY, Carron C, Zhang HW, Shi DL. Down syndrome critical region protein 5 regulates membrane localization of Wnt receptors, Dishevelled stability and convergent extension in vertebrate embryos. Development. 2009; 136: 2121-1.

(16.) Ferrando-Miguel R, Cheon MS, Yang JW, Lubec G. Overexpression of transcription factor BACH1 in fetal Down syndrome brain. J Neural Transm Suppl. 2003; 67: 193-205.

(17.) Richard C, Drevon C, Canto PY, Villain G, Bollerot K, Lempereur A, et al. Endothelio-Mesenchymal Interaction Controls runx1 Expression and Modulates the notch Pathway to Initiate Aortic Hematopoiesis. Dev Cell. 2013; 24: 600-11.

(18.) Giambra V, Jenkins CR, Wang H, Lam SH, Shevchuk OO, Nemirovsky O, et al. NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-? and reactive oxygen species. Nat Med. 2012; 18(11): 1693-8.

(19.) Wang W, Zhu JZ, Chang KT, Min KT. DSCR1 interacts with FMRP and is required for spine morphogenesis and local protein synthesis. EMBO J. 2012; 31(18): 3655-66.

(20.) Ermak G, Pritchard MA, Dronjak S, Niu B, Davies KJ. Do RCAN1 proteins link chronic stress with neurodegeneration. FASEB J. 2011; 25(10): 3306-11.

(21.) Guedj F, Pereira PL, Najas S, Barallobre MJ, Chabert C, Souchet B, et al. DYRK1A: a master regulatory protein controlling brain growth. Neurobiol Dis. 2012; 46(1): 190-200.

(22.) Park J, Oh Y, Chung KC. Two key genes closely implicated with the neuropathological characteristics in Down syndrome: DYRK1A and RCAN1. BMB Rep. 2009; 42(1): 6-15.

(23.) Packard MG, Goodman J. Emotional arousal and multiple memory systems in the mammalian brain. Front Behav Neurosci. 2012; 6: 14.

(24.) Ishizu T, Zeki S. Toward a brain-based theory of beauty. PLoS ONE. 2011; 6: 21852.

(25.) Wegiel J, Gong CX, Hwang YW. The role of DYRK1A in neurodegenerative diseases. FEBS J. 2011; 278: 236-45.

(26.) Grahn JA, Parkinson JA, Owen AM. The cognitive functions of the caudate nucleus. Prog Neurobiol. 2008; 86(3): 141-55.

(27.) Kistler P, Ropper A, Martin J. Enfermedades cerebrovasculares. En: Fauci A, Braunwald E, Kasper D, Hauser S, Longo D, Jameson L, Loscalzo J (eds.). Harrison Principios de Medicina Interna. 17a edicion. Barcelona: McGraw-Hill; 2010. pp. 2570-96.

(28.) Dauphinot L, Lyle R, Rivals I, Dang MT, Moldrich RX, Golfier G, et al. The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome. Hum Mol Genet. 2005; 14: 373-84.

(29.) Potier MC, Rivals I, Mercier G, Ettwiller L, Moldrich RX, Laffaire J, et al. Transcriptional disruptions in Down syndrome: a case study in the Ts1Cje mouse cerebellum during post-natal development. J Neurochem. 2006; 97(1): 104-9.

(30.) Minami T. Calcineurin-NFAT activation and DSCR-1 autoinhibitory loop: how is homoeostasis regulated? J Biochem. 2014; 155: 217-26.

(31.) Arron JR, et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature. 2006; 441: 595-600.

Julio Cesar Montoya [1,3], Dianora Fajardo [2], Angela Pena [2], Adalberto Sanchez [1], Martha C Dominguez [1,2], Jose Maria Satizabal [1], Felipe Garcia-Vallejo [1,2]

[1] Department of Physiological Sciences, School of Basic Sciences, Faculty of Health, Universidad del Valle.

[2] Laboratory of Molecular Biology and Pathogenesis LABIOMOL. Universidad del Valle, Cali, Colombia.

[3] Faculty of Basic Sciences, Universidad Autonoma de Occidente, Cali, Colombia.

Montoya JC, Fajardo D, Pena A, Sanchez A, Dominguez MC, Satizabal JM, Garcia-Vallejo F. Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain. Colomb Med. 2014; 45(4): 154-61.

Corresponding author:

Felipe Garcia-Vallejo. Scientific Director of the Laboratory of Molecular Biology and Pathogenesis. Department of Physiological Sciences. School of Basic Sciences. Faculty of Health. University of Valle. Calle. 4B#36-00. Cali, Colombia. A.A 25360. Phone: +57 2 5140054. Fax: +57 2 5185617. E-mail: labiomol@gmail.com.

Table 1. Summary of the protein/coding genes located at HSA21/DSCR
including in the present work.

Gene ID *   Symbol *      Name *

1827        DSCR1/RCAN1   RCAN1 regulator of calcineurin 1
418520      DSCR2/PSMG1   Proteasome (prosome, macropain)
                            assembly  chaperone 1
10311       DSCR3         Down syndrome critical region gene 3
10281       DSCR4         Down syndrome critical region gene 4
51227       DSCR5/PIGP    Phosphatidylinositol glycan anchor
                            biosynthesis, class P
53820       DSCR6         Down syndrome critical region gene 6

84677       DSCR8         Down syndrome critical region gene 8

259234      DSCR10        Down syndrome critical region gene 10
54102       CLIC6         Chloride intracelular channel 6
25825       BACE2         Beta-site APP-cleaving enzyme 2

861         RUNX1         Runt-related transcription factor 1

6493        SIM2          Single-minded homolog 2 (Drosophila)

1859        DYRK1A        Dual-specificity tyrosine-(Y)-
                            phosphorylation regulated kinase 1A
54014       BRWD1         Bromodomain and WD repeat domain
                            containing 1
6450        SH3BGR        SH3 domain binding glutamic acid-rich
                            protein
1826        DSCAM         Down syndrome cell adhesion molecule

3275        PRMT2         Protein arginine methyltransferase 2
2114        ETS2          v-etserythroblastosis virus E26
                            oncogenehomolog 2 (avian)

3763        KCNJ6         Potassium inwardly-rectifying channel,
                            subfamily J, member 6

Gene ID *   Symbol *      Locus *            Molecular Proccess *

1827        DSCR1/RCAN1   21q22.1            Signal transduction
418520      DSCR2/PSMG1   21q22.3            Proteasome assembly

10311       DSCR3         21q22.2            Vacuolar transport
10281       DSCR4         21q22.2            Biological process
51227       DSCR5/PIGP    21q22.2            Post-translational
                                               protein modification
53820       DSCR6         21q22.2            Negative regulation of
                                               transcription from
                                               RNA polymerase II
                                               promoter
84677       DSCR8         21q22.2            Oncogenesis in some
                                               type de tumors
259234      DSCR10        21q22.13           Biological process
54102       CLIC6         21q22.12           Ion transport
25825       BACE2         21q22.3            Membrane protein
                                               ectodomain
                                               proteolysis
861         RUNX1         21q22.3            Central nervous system
                                               development
6493        SIM2          21q22.2-21q22.13   Transcription
                                               DNA-dependent
1859        DYRK1A        21q22.13           Protein phosphorylation
54014       BRWD1         21q22.2            Transcription
                                               DNA-dependent
6450        SH3BGR        21q22.3            Protein complex
                                               assembly
1826        DSCAM         21q22.2            Nervous system
                                               development
3275        PRMT2         21q22.3            Signal transduction
2114        ETS2          21q22.3-21q22.2    Positive regulation of
                                               transcription from
                                             RNA polymerase II
                                               promoter
3763        KCNJ6         21q22.1            Synaptic transmission

* Gene ID, name and and information about the molecular process of
each gene, was obtained from Gene Entrez database
(http://www/ncbi/nlm/nih.gov/gene/).

Table 2. Names and symbols of different structures of Limbic Lobe and
Cerebral Nuclei.

Structure Name                                   Symbol

Cerebral Nuclei

Caudate nuclei head-left                          CNH-l
Caudate nuclei head-right                         CNH-r
Caudate nuclei tail-left                          CNT-l
Caudate nuclei tail-right                         CNT-r
Putamen left                                       Pu-l
Putamen right                                      Pu-r
Nucleus accumbes left                              NA-l
Nucleus accumbes right                             NA-r
Globus pallidus external left                     GPE-l
Globus pallidus external right                    GPE-r
Globus pallidus internal left                     GPI-l
Globus pallidus internal right                    GPI-R
Septal nuclei left                               SptN-l
Septal nuclei right                              SptN-r
Basal forebrain substantia innominata left      BFbSI-l
Basal forebrain substantia innominata right     BFbSI-r
Claustrum left                                      C-L
Claustrum right                                     C-r
Amigdala transition zone                            ATZ
Amigdala basolateral left                         ABL-l
Amigdala basomedial right                         ABM-r
Central amigdala nucleus                            CAN
Medial amigdala                                      MA
Left nucleus amigdala                              AN-l

Limbic Lobe

Short insular gyrus                                 SIG
Cyngulate girus, frontal                           CgGf
Cyngulate girus, parietal                       CgG-Par
Dental gyrus left                                 DG-l
Central area 1 left                               CA1-l
Central area 1 right                             CA-1 r
Central area 2 left                               CA2-l
Central area 2 right                             CA-2 r
Central area 3 left                               CA3-l
Central area 3 right                             CA-3 r
Central area 4 left                              CA-4-l
Central area 4 right                             CA-4 r
Subiculum left                                     Su-l
Subiculum right                                    Su-r
Parahipocampus gyrus left                         PHG-l
Parahipocampus gyrus -Cos-left                PHG-cos-l
Parahipocampus gyrusRight                         PHG-r
Parahipocampus gyrus -Cos-right               PHG-cos-r

The names were extracted from the Allen Institute for Brain Sciences,
available at http://human.brainmap.org/content/WholeBrainMicroarray.

Figure 1. Global expression profiles of nineteen genes located at the
HAS21-DSCR along different sustructures of cerebral nuclei and limbic
lobe. (A) Genes overexpressed per brain substructure. (B). Genes
underexpressed per brain substructure. The mean z-score of DSCR genes
was obtained from transcription data of several DNA microarrays
consigned in the public database of the Allen Human Brain Atlas
(http://www-alleninstitute-org)-Caudate nuclei head-left (CNH-l),
Caudate nuclei head-right (CNH-r), Caudate nuclei tail-left (CNT-l),
Caudate nuclei tail-right (CNT-r), Putamen left (Pu-l), Putamen right
(Pu-r), Globus pallidus external left (GPE-l), Globus pallidus
internal (GPI), Dental gyrus (DG), Central area 1 (CA1), Central area
2 (CA2), Central area 3 (CA3) and Central area 4 (CA-4).

A

       DSCR3   DSCR6   PIGP    CLIC6   DYRK1A   RUNX1   SH38GR

CA2    1,95
CA1    3,0
DG                                     1,62
Pu             3,00
Acb            1,66
TCd            3,00
HCd            3,00
BCd            3,00
Gpi                    2,03                     1,58     1,62
Gpe    2,56            2,81            1,65

       PRMT2   KCNJ6

CA2
CA1
DG
Pu
Acb
TCd
HCd
BCd
Gpi    1,54
Gpe    2,25

B

       PSMG1   DSCR6   PIGP    BACE2   KCNJ6   PRMT2

CA4            -1,79
CA3            -2,70   -1,84
CA2            -2,47   -2,03
CA1            -1,85
DG             -2,41           -1,82
Pu    -2,80                            -2,76
Acb   -2,23
TCd   -2,82    -1,90                   -2,76
HCd                                    -2,47
BCd   -2,52                            -3,10
Gpi            -1,82
Gpe

Note: Table made from bar graph.
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Author:Montoya, Julio Cesar; Fajardo, Dianora; Pena, Angela; Sanchez, Adalberto; Dominguez, Martha C.; Sati
Publication:Colombia Medica
Date:Oct 1, 2014
Words:5330
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