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Current Opinion in Genetics & Development

Yan Hao, Catherine Collins
Axonal damage and loss are common and negative consequences of neuronal injuries, and also occur in some neurodegenerative diseases. For neurons to have a chance to repair their connections, they need to survive the damage, initiate new axonal growth, and ultimately establish new synaptic connections. This review discusses how recent work in Drosophila models have informed our understanding of the cellular pathways used by neurons to respond to axonal injuries. Similarly to mammalian neurons, Drosophila neurons appear to be more limited in their capacity regrow (regenerate) damaged axons in the central nervous system, but can undergo axonal regeneration to varying extents in the peripheral nervous system...
February 20, 2017: Current Opinion in Genetics & Development
Xian Qu, Kylee M Peterson, Keiko U Torii
Stomata have significantly diversified in nature since their first appearance around 400 million years ago. The diversification suggests the active reprogramming of molecular machineries of stomatal development during evolution. This review focuses on recent progress that sheds light on how this rewiring occurred in different organisms. Three specific aspects are discussed in this review: (i) the evolution of the transcriptional complex that governs stomatal state transitions; (ii) the evolution of receptor-ligand pairs that mediate extrinsic signaling; and (iii) the loss of stomatal development genes in an astomatous angiosperm...
February 17, 2017: Current Opinion in Genetics & Development
Sandra Tenreiro, Vanessa Franssens, Joris Winderickx, Tiago Fleming Outeiro
The aging of the human population is resulting in an increase in the number of people afflicted by neurodegenerative disorders such as Parkinson's disease (PD), creating tremendous socio-economic challenges. This requires the urgent for the development of effective therapies, and of tools for early diagnosis of the disease. However, our understanding of the molecular mechanisms underlying PD pathogenesis is still incomplete, hampering progress in those areas. In recent years, the progression made in genetics has considerably contributed to our knowledge, by identifying several novel PD genes...
February 16, 2017: Current Opinion in Genetics & Development
Melissa Gymrek
Short tandem repeats (STRs) are some of the fastest mutating loci in the genome. Tools for accurately profiling STRs from high-throughput sequencing data have enabled genome-wide interrogation of more than a million STRs across hundreds of individuals. These catalogs have revealed that STRs are highly multiallelic and may contribute more de novo mutations than any other variant class. Recent studies have leveraged these catalogs to show that STRs play a widespread role in regulating gene expression and other molecular phenotypes...
February 14, 2017: Current Opinion in Genetics & Development
Julia Bussmann, Erik Storkebaum
Peripheral neuropathies are characterized by degeneration of peripheral motor, sensory and/or autonomic axons, leading to progressive distal muscle weakness, sensory deficits and/or autonomic dysfunction. Acquired peripheral neuropathies, e.g., as a side effect of chemotherapy, are distinguished from inherited peripheral neuropathies (IPNs). Drosophila models for chemotherapy-induced peripheral neuropathy and several IPNs have provided novel insight into the molecular mechanisms underlying axonal degeneration...
February 14, 2017: Current Opinion in Genetics & Development
Naoki Hisamoto, Kunihiro Matsumoto
Axon regeneration after nerve injury is a conserved biological process in many animals, including humans. The nematode Caenorhabditis elegans (C. elegans) has recently emerged as a genetically tractable model for studying regenerative responses in neurons. Extensive studies over several years using this organism have revealed a number of intrinsic and extrinsic signal transduction cascades that regulate axon regeneration, and these are found to be conserved from worms to humans. Further studies have demonstrated that these cascades consist of several signaling networks that ultimately merge into the c-Jun N-terminal kinase (JNK) cascade...
February 14, 2017: Current Opinion in Genetics & Development
Alexander J Whitworth, Leo J Pallanck
Mitochondria are essential organelles that provide cellular energy and buffer cytoplasmic calcium. At the same time they produce damaging reactive oxygen species and sequester pro-apoptotic factors. Hence, eukaryotes have evolved exquisite homeostatic processes that maintain mitochondrial integrity, or ultimately remove damaged organelles. This subject has garnered intense interest recently following the discovery that two Parkinson's disease genes, PINK1 and parkin, regulate mitochondrial degradation (mitophagy)...
February 14, 2017: Current Opinion in Genetics & Development
Yu-Chun Wang, Elsa Lauwers, Patrik Verstreken
Proteome integrity is maintained by a coordinated network of molecular chaperones, by protein degradation machineries and by their regulators. Numerous human pathologies are considered as diseases of compromised protein homeostasis (proteostasis), including neurodegeneration. These are characterized by the accumulation of neuronal protein aggregates and by synaptic defects followed by loss of connectivity and cell death. While this suggests that synaptic terminals are particularly sensitive to proteostasis imbalance, our understanding of protein turnover mechanisms and regulation at the synapse remains limited...
February 14, 2017: Current Opinion in Genetics & Development
Kevin Yum, Eric T Wang, Auinash Kalsotra
Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease primarily characterized by myotonia and progressive muscle weakness. The pathogenesis of DM involves microsatellite expansions in noncoding regions of transcripts that result in toxic RNA gain-of-function. Each successive generation of DM families carries larger repeat expansions, leading to an earlier age of onset with increasing disease severity. At present, diagnosis of DM is challenging and requires special genetic testing to account for somatic mosaicism and meiotic instability...
February 14, 2017: Current Opinion in Genetics & Development
Nan Zhang, Tetsuo Ashizawa
More than 30 incurable neurological and neuromuscular diseases are caused by simple microsatellite expansions consisted of 3-6 nucleotides. These repeats can occur in non-coding regions and often result in a dominantly inherited disease phenotype that is characteristic of a toxic RNA gain-of-function. The expanded RNA adopts unusual secondary structures, sequesters various RNA binding proteins to form insoluble nuclear foci, and causes cellular defects at a multisystem level. Nuclear foci are dynamic in size, shape and colocalization of RNA binding proteins in different expansion diseases and tissue types...
February 13, 2017: Current Opinion in Genetics & Development
James Shorter
Protein misfolding and aggregation unify several devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. There are no effective therapeutics for these disorders and none that target the reversal of the aberrant protein misfolding and aggregation that cause disease. Here, I showcase important advances to define, engineer, and apply protein disaggregases to mitigate deleterious protein misfolding and counter neurodegeneration. I focus on two exogenous protein disaggregases, Hsp104 from yeast and gene 3 protein from bacteriophages, as well as endogenous human protein disaggregases, including: (a) Hsp110, Hsp70, Hsp40, and small heat-shock proteins; (b) HtrA1; and (c) NMNAT2 and Hsp90...
February 13, 2017: Current Opinion in Genetics & Development
Dubravka Pezic, Samuel L Weeks, Suzana Hadjur
Recent years have witnessed a dramatic expansion in our understanding of gene control. It is now widely appreciated that the spatial organization of the genome and the manner in which genes and regulatory elements are embedded therein has a critical role in facilitating the regulation of gene expression. The loop structures that underlie chromosome organization are anchored by cohesin complexes. Several components of the cohesin complex have multiple paralogs, leading to different levels of cohesin complex variants in cells...
February 9, 2017: Current Opinion in Genetics & Development
Marc Tollis, Joshua D Schiffman, Amy M Boddy
Cancer suppression is an important feature in the evolution of large and long-lived animals. While some tumor suppression pathways are conserved among all multicellular organisms, others mechanisms of cancer resistance are uniquely lineage specific. Comparative genomics has become a powerful tool to discover these unique and shared molecular adaptations in respect to cancer suppression. These findings may one day be translated to human patients through evolutionary medicine. Here, we will review theory and methods of comparative cancer genomics and highlight major findings of cancer suppression across mammals...
February 2, 2017: Current Opinion in Genetics & Development
Derick C Hoskinson, Adrian M Dubuc, Heather Mason-Suares
Accurate and consistent variant classification is required for Precision Medicine. But clinical variant classification remains in its infancy. While recent guidelines put forth jointly by the American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) for the classification of Mendelian variants has advanced the field, the degree of subjectivity allowed by these guidelines can still lead to inconsistent classification across clinical molecular genetic laboratories. In addition, there are currently no such guidelines for somatic cancer variants, only published institutional practices...
January 31, 2017: Current Opinion in Genetics & Development
Jasper Wouters, Zeynep Kalender Atak, Stein Aerts
Gene regulatory networks determine cellular identity. In cancer, aberrations of gene networks are caused by driver mutations that often affect transcription factors and chromatin modifiers. Nevertheless, gene transcription in cancer follows the same cis-regulatory rules as normal cells, and cancer cells have served as convenient model systems to study transcriptional regulation. Tumours often show regulatory heterogeneity, with subpopulations of cells in different transcriptional states, which has important therapeutic implications...
January 24, 2017: Current Opinion in Genetics & Development
Daphne Tsoucas, Guo-Cheng Yuan
The advent of single-cell sequencing has been revolutionary to the field of cancer genomics. Perfectly suited to capture cancer's heterogeneous nature, single-cell analyses provide information bulk sequencing could never hope to uncover. Many mechanisms of cancer have yet to be fully understood, and single-cell approaches are showing promise in their abilities to uncover these mysteries. Here we focus on the most recent single-cell methods for cancer genomics, and how they are not only providing insights into the inner workings of cancer, but are also transforming individualized therapy and non-invasive monitoring and diagnosis...
January 23, 2017: Current Opinion in Genetics & Development
Timothy M Butler, Paul T Spellman, Joe Gray
The development of new circulating-tumor DNA (ctDNA) analysis techniques has led to an explosion of studies demonstrating exciting clinical applications. Non-invasive genotyping can characterize mutations of interest without the need for an invasive biopsy. Serial ctDNA monitoring can assess response to treatment, and potentially identify mechanisms of resistance. Perhaps most excitingly, sensitive ctDNA analysis methods allow for detection of minimally residual disease, predicting recurrence months before clinical presentation...
January 23, 2017: Current Opinion in Genetics & Development
Franziska Reiter, Sebastian Wienerroither, Alexander Stark
Differential gene expression gives rise to the many cell types of complex organisms. Enhancers regulate transcription by binding transcription factors (TFs), which in turn recruit cofactors to activate RNA Polymerase II at core promoters. Transcriptional regulation is typically mediated by distinct combinations of TFs, enabling a relatively small number of TFs to generate a large diversity of cell types. However, how TFs achieve combinatorial enhancer control and how enhancers, enhancer-bound TFs, and the cofactors they recruit regulate RNA Polymerase II activity is not entirely clear...
January 19, 2017: Current Opinion in Genetics & Development
J Omar Yáñez-Cuna, Bas van Steensel
Lamina-associated domains (LADs) are large genomic regions that interact with the nuclear lamina (NL) and help to guide the spatial folding of chromosomes in the interphase nucleus. LADs have been linked to gene repression and other functions. Recent studies have begun to uncover some of the molecular players that drive LAD-NL interactions. A picture emerges in which DNA sequence, chromatin components and nuclear lamina proteins play an important role. Complementary to this, imaging and single-cell genomics approaches have revealed that some LAD-NL interactions are variable from cell to cell, while others are very stable...
January 17, 2017: Current Opinion in Genetics & Development
D'Juan T Farmer, Michael T McManus
The surface ectoderm is the source of ectodermal appendages including hair, teeth, and many glands. The development and function of ectodermal appendages has been researched extensively, but many of the molecular mechanisms that govern the developmental programs of ectodermal appendages remain elusive. While several protein-coding genes are established as key regulators of ectodermal appendage development, the role of noncoding RNAs is an emerging area of investigation. This review highlights recent advances in studies of microRNA-mediated control of ectodermal appendage development using mouse models...
January 16, 2017: Current Opinion in Genetics & Development
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