Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome

Original article:

Children with Down syndrome (DS) show a spectrum of clinical anomalies, including cognitive impairment, cardiac malformations, and craniofacial dysmorphy. Moreover, hematologists have also noted that these children commonly show macrocytosis, abnormal platelet counts, and an increased incidence of transient myeloproliferative disease (TMD), acute megakaryocytic leukemia (AMKL), and acute lymphoid leukemia (ALL).

In this review, we summarize the clinical manifestations and characteristics of these leukemias, provide an update on therapeutic strategies and patient outcomes, and discuss the most recent advances in DS-leukemia research. With the increased knowledge of the way in which trisomy 21 affects hematopoiesis and the specific genetic mutations that are found in DS-associated leukemias, we are well on our way toward designing improved strategies for treating both myeloid and lymphoid malignancies in this high-risk population.

(Via Blood recent issues.)

Down syndrome--recent progress and future prospects

Original article:

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge.

Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype-phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.

(Via Human Molecular Genetics - current issue.)

Regulation of APC/C Activity in Oocytes by a Bub1-Dependent Spindle Assembly Checkpoint

Original article

Barry E. McGuinness, Martin Anger, Anna Kouznetsova, Ana M. Gil-Bernabé, Wolfgang Helmhart, Nobuaki R. Kudo, Annelie Wuensche, Stephen Taylor, Christer Hoog, Bela Novak, Kim Nasmyth.

Summary

Missegregation of chromosomes during meiosis in human females causes aneuploidy, including trisomy 21, and is thought also to be the major cause of age-related infertility [1]. Most errors are thought to occur at the first meiotic division. The high frequency of errors raises questions as to whether the surveillance mechanism known as the spindle assembly checkpoint (SAC) that controls the anaphase-promoting complex or cyclosome (APC/C) operates effectively in oocytes.

Experimental approaches hitherto used to inactivate the SAC in oocytes suffer from a number of drawbacks.Bub1 protein was depleted specifically in oocytes with a Zp3-Cre transgene to delete exons 7 and 8 from a floxed BUB1F allele. Loss of Bub1 greatly accelerates resolution ofchiasmata and extrusion of polar bodies. It also causes defective biorientation of bivalents, massive chromosome missegregation at meiosis I, and precocious loss of cohesion between sister centromeres.

By using a quantitative assay forAPC/C-mediated securin destruction, we show that the APC/C is activated in an exponential fashion, with activity peaking 1213 hr after GVBD, and that this process is advanced by 5hr in oocytes lacking Bub1. Importantly, premature chiasmata resolution does not occur in Bub1-deficient oocytes also lacking either the APC/C's Apc2 subunit or separase.

Finally, we show that Bub1's kinase domain is not required to delay APC/C activation.We conclude that far from being absent or ineffective, the SAC largely determines the timing of APC/C and hence separase activation in oocytes, delaying it for about 5 hr.

(Via Current Biology.)

Current use of medical eponyms - a need for global uniformity in scientific publications

Original article

Background:

Although eponyms are widely used in medicine, they arbitrarily alternate between the possessive and nonpossessive forms. As very little is known regarding extent and distribution of this variation, the present study was planned to assess current use of eponymous term taking 'Down syndrome' and 'Down's syndrome' as an example.

Methods:

This study was carried out in two phases - first phase in 1998 and second phase in 2008. In the first phase, we manually searched the terms 'Down syndrome' and 'Down's syndrome' in the indexes 70 medical books, and 46 medical journals. In second phase, we performed PubMed search with both the terms, followed by text-word search for the same.

Results:

In the first phase, there was an overall tilt towards possessive form - 62(53.4%) 'Down's syndrome' versus 54(46.6%) 'Down syndrome.' However, the American publications preferred the nonpossesive form when compared with their European counterpart (40/50 versus 14/66; P<0.001). In the second phase, PubMed search showed, compared to "Down syndrome," term "Down's syndrome" yielded approximately 5% more articles. The text-word search of both forms between January 1970 and June 2008 showed a gradual shift from "Down's syndrome" to "Down syndrome," and over the last 20 years, the frequency of the former was approximately halved (33.7% versus 16.5%; P<0.001). The abstracts having possessive form were mostly published from the European countries, while most American publications used nonpossesive form consistently.

Conclusions:

Inconsistency in the use of medical eponyms remains a major problem in literature search. Because of linguistic simplicity and technical advantages, the nonpossessive form should be used uniformly worldwide."

(Via BioMed Central - Latest articles.)

Heterochromatic Threads Connect Oscillating Chromosomes during Prometaphase I in Drosophila Oocytes

Link to original article:

Proper chromosome segregation is essential during the production of eggs and sperm. Chromosome missegregation during meiosis results in the lethality of the offspring or in children carrying extra copies of a given chromosome (for example, Down syndrome). Recombination results in homologous chromosomes becoming physically interlocked in a manner that is normally sufficient to ensure proper segregation. Chromosomes that fail to undergo recombination require additional mechanisms to ensure their proper segregation.

In Drosophila melanogaster oocytes we show that chromosomes that fail to recombine undergo dynamic movements on the meiotic spindle prior to their proper segregation. Although previous studies had shown that non-recombinant chromosomes move to opposite sides of the developing meiotic spindle, we show that these chromosomes can cross the spindle and re-associate with their homologs to attempt reorientation.

Additionally, we observed threads connecting separated non-recombinant chromosomes that contained heterochromatic DNA and passenger complex proteins. These threads could assist the non-recombinant chromosomes in locating their homologs during their dynamic movements on the spindle. These chromosome movements and the heterochromatic threads are likely part of the mechanism ensuring proper segregation of nonexchange chromosomes.

[Reviews] Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes

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Cadherins and the immunoglobulin (Ig) proteins give rise to a multitude of surface receptors, which function as diverse cell adhesion molecules (CAMs) or signal-transducing receptors. These functions are often interdependent, and rely on a high degree of specificity in homophilic binding as well as heterophilic interactions. The Drosophila receptor Dscam is an exceptional example of homophilic binding specificity involved in a number of important biological processes, such as neural wiring and innate immunity.

Combinatorial use of alternatively spliced Ig-domains enables the generation of an estimated 18,000 isoform-specific homophilic receptor pairs. Although isoform diversity of Dscam is unique to arthropods, recent genetic analysis of vertebrate DSCAM (Down Syndrome Cell Adhesion Molecule) genes has revealed an intriguing conservation of molecular functions underlying neural wiring.

This review covers the multiple functions of Dscam across different species highlighting its remarkable versatility as well as its conserved basic functions in neural development. We discuss how an unprecedented expansion of complex alternative splicing has been uniquely employed by arthropods to generate diverse surface receptors, important for cell-cell communication, molecular self-recognition in neurons, and innate immune defenses. We end with a speculative hypothesis reconciling the striking differences in Dscam and DSCAM gene structures with their conserved functions in molecular recognition underlying neural circuit formation.

(Via Genes & Development current issue.)

Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice

Link to original article

Background In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the alpha-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology.

Results: To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the alpha-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme. As compared to non-transgenic wild-type mice, in ADAM10 transgenic mice 355 genes, and in dnADAM10 mice 143 genes were found to be differentially expressed. A higher number of genes was differentially regulated in double-transgenic mouse strains additionally expressing the human APP[V717I] mutant.

Overexpression of proteolytically active ADAM10 affected several physiological pathways, such as cell communication, nervous system development, neuron projection as well as synaptic transmission. Although ADAM10 has been implicated in Notch and beta-catenin signaling, no significant changes in the respective target genes were observed in adult ADAM10 transgenic mice.

Real-time RT-PCR confirmed a downregulation of genes coding for the inflammation-associated proteins S100a8 and S100a9 induced by moderate ADAM10 overexpression. Overexpression of the dominant-negative form dnADAM10 led to a significant increase in the expression of the fatty acid-binding protein Fabp7, which also has been found in higher amounts in brains of Down Syndrome patients.

Conclusion: In general, there was only a moderate alteration of gene expression in ADAM10 overexpressing mice. Genes coding for pro-inflammatory or pro-apoptotic proteins were not over-represented among differentially regulated genes. Even a decrease of inflammation markers was observed. These results are further supportive for the strategy to treat AD by increasing the alpha-secretase activity.

(Via BioMed Central - Latest articles.)

[Neuroscience] DSCAM functions as a netrin receptor in commissural axon pathfinding

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Down syndrome cell adhesion molecule (DSCAM) is required for axon guidance and dendrite arborization. How DSCAM functions in vertebrates is not well understood. Here we show that DSCAM is expressed on commissural axons and interacts with Netrin-1, a prototypical guidance cue for commissural axons. The knockdown of DSCAM by specific siRNA or blockage of DSCAM signaling by overexpression of a mutant lacking its intracellular domain inhibits netrin-induced axon outgrowth and commissural axon turning in vitro. SiRNA-mediated knockdown of DSCAM in ovo causes defects in commissural axon projection and pathfinding. In transfected cells, DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling in activating phosphorylation of Fyn and Pak1. These findings demonstrate an essential role of vertebrate DSCAM in axon guidance, indicating that DSCAM functions as a receptor of netrin-1. Our data suggest previously unexpected complexity in receptors that mediate vertebrate netrin signaling.

(Via Proceedings of the National Academy of Sciences recent issues.)