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Pest Manag Sci,
2001]
Chitin is an abundant biologically important aminopolysaccharide composed of N-acetyl-D-glucosamine units. Individual polymers, which are synthesized intracellularly by chitin synthase (CS), a membrane-bound glycosyl transferase, are translocated across the plasma membrane and coalesce to form rigid crystallites. These crystallites, inter alia, are integral parts of septa and cell walls in yeast and filamentous fungi, respectively, and of cuticles in invertebrates, notably crustaceans and insects. Despite decades of intensive research, many events associated with the complexity of chitin formation and deposition are still obscure, or only partially understood. The list includes the hormonal control of CS at the transcriptional and translational levels as well as the post-translational CS packaging; trafficking and guidance of CS clusters to proper sites in the cells and their intricate insertion into the plasma membranes; activation of the catalytic step and its control or modulation; and translocation of chitin chains across cell membranes, their orientation, fibrillogenesis and association with other extracellular structural components such as polysaccharides (fungi) and cuticular proteins (insects). Also the precise biochemical lesions inflicted by CS inhibitors, such as the acylurea insect growth regulators, are largely unclear. The recent isolation and sequencing of insect CS genes should help in elucidating various aspects of chitin biochemistry and inhibition. In particular, the large number of transmembrane segments, characteristic of the insect CS, are speculated to be involved in chitin translocation and are expected to shed light on the mode of action of acylurea insecticides.
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Biol Bull,
1998]
The identification of the molecular components of the developmental neurogenic programs in different organisms has revealed an astounding degree of conservation across phylogeny, suggesting that the basic mechanisms of neural development have also been conserved in evolution. One class of conserved neural regulatory genes, the LIM homeobox genes, encode transcription factors with two Zn-finger-like LIM domains and a DNA-binding homeodomain. Vertebrate members of this class have been implicated in neurogenesis by correlative expression evidence: e.g., the combinatorial expression of LIM homeobox genes in the vertebrate spinal cord suggested a "LIM-code" for specific motorneuronal targeting choices. Genetic analysis in Drosophila also demonstrated their essential role in axon pathfinding and the determination of neurotransmitter identity. The genome of the nematode Caenorhabditis elegans is almost completely sequenced, thus allowing the analysis of complete gene families in a metazoan organism. C. elegans contains seven LIM homeobox genes. Almost all C. elegans LIM homeobox genes fall into subclasses that are defined by the presence of similar genes from arthropods and vertebrates, suggesting a common origin for different subclasses of LIM homeobox genes.
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Trends Genet,
2000]
Homeobox genes play fundamental roles in development. They can be subdivided into several subfamilies, one of which is the LIM-homeobox subfamily. The primary structure of LIM-homeobox genes has been remarkably conserved through evolution. Have their functions similarly been conserved? A host of new data has been derived from mutational analysis in diverse organisms, such as nematodes, flies and vertebrates. These studies have revealed a prominent involvement of LIM-homeodomain proteins in tissue patterning and differentiation, and their function in neural patterning is evident in all organisms studied to date. Here, we summarize the recent findings on LIM-homeobox gene function, compare the function of these genes from different organisms and describe specific co-factor requirements.
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Curr Biol,
2003]
Recent studies highlight the striking similarity between vertebrate focal adhesion plaques and Caenorhabditis elegans muscle adhesion structures and position LIM domain proteins as central players at focal adhesions.
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Neurotoxicology,
2008]
Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders. Excessive exposure to Mn can cause Parkinson''s disease-like syndrome; patients typically exhibit extrapyramidal symptoms that include tremor, rigidity and hypokinesia [Calne DB, Chu NS, Huang CC, Lu CS, Olanow W. Manganism and idiopathic parkinsonism: similarities and differences. Neurology 1994;44(9):1583-6; Dobson AW, Erikson KM, Aschner M. Manganese neurotoxicity. Ann NY Acad Sci 2004;1012:115-28]. Mn-induced motor neuron diseases have been the subjects of numerous studies; however, this review is not intended to discuss its neurotoxic potential or its role in the etiology of motor neuron disorders. Rather, it will focus on Mn uptake and transport via the orthologues of the divalent metal transporter (DMT1) and its possible implications to Mn toxicity in various categories of eukaryotic systems, such as in vitro cell lines, in vivo rodents, the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera L., the nematode, Caenorhabditis elegans and the baker''s yeast, Saccharomyces cerevisiae.
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Biomolecules,
2015]
DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER) lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice and C. elegans has shed new light on the mechanisms through which developing and aging animals respond to persistent DNA damage. The various NER mouse mutants have served as important disease models for Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), while the traceable genetics of C. elegans have allowed the mechanistic delineation of the distinct outcomes of genome instability in metazoan development and aging. Intriguingly, highly conserved longevity assurance mechanisms respond to transcription-blocking DNA lesions in mammals as well as in worms and counteract the detrimental consequences of persistent DNA damage. The insulin-like growth factor signaling (IIS) effector transcription factor DAF-16 could indeed overcome DNA damage-driven developmental growth delay and functional deterioration even when DNA damage persists. Longevity assurance mechanisms might thus delay DNA damage-driven aging by raising the threshold when accumulating DNA damage becomes detrimental for physiological tissue functioning.
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Biochim Biophys Acta Gene Regul Mech,
2019]
The eukaryotic genome is organized at varying levels into chromosome territories, transcriptional compartments and topologically associating domains (TADs), which are architectural features largely shared between different cell types and across species. In contrast, within TADs, chromatin loops connect enhancers and their target genes to establish unique transcriptomes that distinguish cells and tissues from each other and underlie development and differentiation. How these tissue-specific and temporal stage-specific long-range contacts are formed and maintained is a fundamental question in biology. The widely expressed Lim domain binding 1 protein, LDB1, plays a critical role in connecting enhancers and genes by forming complexes with cell-type specificity across diverse developmental pathways including neurogenesis, cardiogenesis, retinogenesis and hematopoiesis. Here we review the multiple roles of LDB1 in cell fate determination and in chromatin loop formation, with an emphasis on mammalian systems, to illuminate how LDB1 functions in normal cells and in diseases such as cancer.
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Chromosoma,
2016]
Here, we provide an update of our review on homeobox genes that we wrote together with Walter Gehring in 1994. Since then, comprehensive surveys of homeobox genes have become possible due to genome sequencing projects. Using the 103 Drosophila homeobox genes as example, we present an updated classification. In animals, there are 16 major classes, ANTP, PRD, PRD-LIKE, POU, HNF, CUT (with four subclasses: ONECUT, CUX, SATB, and CMP), LIM, ZF, CERS, PROS, SIX/SO, plus the TALE superclass with the classes IRO, MKX, TGIF, PBC, and MEIS. In plants, there are 11 major classes, i.e., HD-ZIP (with four subclasses: I to IV), WOX, NDX, PHD, PLINC, LD, DDT, SAWADEE, PINTOX, and the two TALE classes KNOX and BEL. Most of these classes encode additional domains apart from the homeodomain. Numerous insights have been obtained in the last two decades into how homeodomain proteins bind to DNA and increase their specificity by interacting with other proteins to regulate cell- and tissue-specific gene expression. Not only protein-DNA base pair contacts are important for proper target selection; recent experiments also reveal that the shape of the DNA plays a role in specificity. Using selected examples, we highlight different mechanisms of homeodomain protein-DNA interaction. The PRD class of homeobox genes was of special interest to Walter Gehring in the last two decades. The PRD class comprises six families in Bilateria, and tinkers with four different motifs, i.e., the PAIRED domain, the Groucho-interacting motif EH1 (aka Octapeptide or TN), the homeodomain, and the OAR motif. Homologs of the co-repressor protein Groucho are also present in plants (TOPLESS), where they have been shown to interact with small amphipathic motives (EAR), and in yeast (TUP1), where we find an EH1-like motif in MAT2.
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WormBook,
2005]
C. elegans vulval development is an intensively studied example of animal organogenesis. A network of intercellular signaling, signal transduction, and transcriptional regulation underlies the precise formation of this organ, which is the connection between the hermaphrodite uterus and the outside of the nematode. A single cell of the somatic gonad, the anchor cell, organizes the development of the vulva from epidermal precursors as well as the physical connection of the epidermis with the uterus. WNT signaling acting via the HOX gene
lin-39 renders six epidermal precursor cells competent to respond to other developmental signals. The anchor cell induces nearby epidermal precursor cells to generate vulval cells via an epidermal growth factor (EGF) signaling pathway. The precise pattern of vulval precursor cell fates involves the graded action of the EGF signaling and LIN-12 (Notch) mediated lateral signaling. EGF promotes the 1 fate while LIN-12 promotes the 2 fate. Both EGF and LIN-12 prevent precursor cells from adopting the 3 fate, which generates non-specialized epidermis. EGF-receptor and Notch signaling are antagonistic: EGF-receptor signaling leads to down-regulation of the Notch-like receptor LIN-12 , while LIN-12 signaling induces negative regulators of EGF-receptor signaling such as MAP kinase phosphatase LIP-1 and the tyrosine kinase ARK-1. The 1 precursor cell generates vulE and vulF mature vulval cells; the pattern of vulE and vulF cells requires an additional signal from the anchor cell as well as WNT signaling. The two 2 precursor cells generate vulA, vulB1, vulB2, vulC and vulD cells but in mirror symmetric polar patterns: ABCD and DCBA. The reversed polarity of the posterior 2 precursor cell lineage requires WNT signaling mediated by both Frizzled class and Ryk class WNT-receptors LIN-17 and LIN-18 , respectively. A network of transcription factors controls the seven mature adult cell types; these include the LIM domain protein LIN-11 , the Pax2/5/8 protein EGL-38 , the zinc finger protein LIN-29 , and the Nkx6.1/6.2 protein COG-1. The anchor cell also patterns nearby uterine cells, via the DSL ligand LAG-2 and LIN-12 , to generate the four
uv1 cells that form the tight connection with the vulva. This connection is initiated by the anchor cell, which invades between the vulF cells in a process analogous to invasive behavior of metastatic tumor cells. During this invasion process, the basement membranes between the gonad and body wall are degraded. The extensive information about vulval development in C. elegans has helped it become a paradigmatic case for identifying and studying a variety of regulatory pathways.