Suzuki M et al. (2013) Dev Growth Differ "Infrared laser-induced gene expression in targeted single cells of Caenorhabditis elegans."

Shimojou M, Toyoda N, Suzuki M, Takagi S

[Dev Growth Differ, 2013]

Since the dawn of transgenic technology some 40years ago, biologists have sought ways to manipulate, at their discretion, the expression of particular genes of interest in living organisms. The infrared laser-evoked gene operator (IR-LEGO) is a recently developed system for inducing gene expression in living organisms in a targeted fashion. It exploits the highly efficient capacity of an infrared laser for heating cells, to provide a high level of gene expression driven by heat-inducible promoters. By irradiating living specimens with a laser under a microscope, heat shock responses can be induced in individual cells, thereby inducing a particular gene, under the control of a heat shock promoter, in specifically targeted cells. In this review we first summarize previous attempts to drive transgene expression in organisms by using heat shock promoters, and then introduce the basic principle of the IR-LEGO system, and its applications.

Wojtovich AP et al. (2012) Exp Gerontol "Ischemic preconditioning: the role of mitochondria and aging."

Nadtochiy SM, Wojtovich AP, Nehrke K, Brookes PS

[Exp Gerontol, 2012]

Aging represents a triple threat for myocardial infarction (MI). Not only does the incidence of MI increase with age, but the heart becomes more susceptible to MI induced damage and protective interventions such as ischemic preconditioning (IPC) become less effective. Therefore, any rational therapeutic strategy must be built around the ability to combat the detrimental effects of ischemia in aged individuals. To accomplish this, we need to develop a better understanding of how ischemic damage, protection, and aging are linked. In this regard, mitochondria have emerged as a common theme. First, mitochondria contribute to cell damage during ischemia-reperfusion (IR) and are central to cell death. Second, the protective signaling pathways activated by IPC converge on mitochondria, and the opening of mitochondrial ion channels alone is sufficient to elicit protection. Finally, mitochondria clearly influence the aging process, and specific defects in mitochondrial activity are associated with age-related functional decline. This review will summarize the effects of aging on myocardial IR injury and discuss relevant and emerging strategies to protect against MI with an emphasis on mitochondrial function.

Freude S et al. (2009) Curr Alzheimer Res "The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: from model organisms to human disease."

Schilbach K, Schubert M, Freude S

[Curr Alzheimer Res, 2009]

In different clinical studies, an association of type 2 diabetes and Alzheimer's disease (AD) has been described. However, the underlying mechanisms are still unclear. One explanation could be that vascular complications of diabetes result in neurodegeneration. Alternatively, the mechanism might be directly related to insulin and insulin-like growth factor(IGF)-1 signaling, leading to the proposal that AD is a "brain-type diabetes". Furthermore, postmortem analyses of brains from patients with AD revealed a markedly downregulated expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1 and IRS-2, and these changes progress with severity of neurodegeneration. These findings raise the question, whether this phenomenon is cause or consequence of neurodegeneration. Recently, Cohen and coworkers have show that knocking down DAF-2 in C. elegans, the homolog of the mammalian IR/IGF-1R, reduces beta-amyloid(Abeta)(1-42) toxicity. Cell based experiments suggest a specific role for the IGF 1/IRS-2 signaling pathway in regulating alpha-/beta-secretase activity. Moreover circulating IGF-1 might influence Abeta clearance from the brain by promoting Abeta transport over the blood brain barrier. Interestingly, brain specific deletion of IRS-2 increases life span, suggesting that long term neuronal IGF-1R signaling might be harmful. Taken together, the data from humans and different model organisms indicate a role of IR/IGF-1R signaling in Abeta metabolism, and clearance as well as longevity. Since more studies are needed to elucidate the impact of insulin and/or IGF-1 treatment in AD, the time to propose these hormones as a potential treatment option for AD has not come yet.

Johnson TE (1983) "Aging in C. elegans."

Johnson TE

[1983]

In 1974, Sydney Brenner published an elegant paper that described the genetic system of Caenorhabditis elegans and led to its use in research on a wide variety of topics, including aging (Brenner, 1974). Its small size (1mm as an adult) and determinate cell lineage has allowed a description of the entire somatic cell lineage from the one-cell stage to the adult (Sulston and Horvitz, 1977; Deppe et al., 1978; Kimble and Hirsh, 1979; Suslton et al., personal communication). Its ease of culture makes it an organism of choice for studies of various aspects of anatomy and physiology, including muscle formation and function (Zengel and Epstein, 1980; Mackenzie and Epstein, 1980), cuticle formation (Cox et al, 1981), neuroanatomy (Ward et al, 1975; Ware et al, 1975; Sulston et al, 1975), and behavior (Dusenbery, 1980). Several genes have been cloned by recombinant DNA techniques ablation (Kimble, 1981; Laufer and von Ehrenstin, 1981) procedures, as well as most of the modern molecular techniques, are in use.

Driesschaert B et al. (2021) J Genet Genomics "Conditional gene expression in invertebrate animal models."

Temmerman L, Mergan L, Driesschaert B

[J Genet Genomics, 2021]

A mechanistic understanding of biology requires appreciating spatiotemporal aspects of gene expression and its functional implications. Conditional expression allows for (ir)reversible switching of genes on or off, with the potential of spatial and/or temporal control. This provides a valuable complement to the more often used constitutive gene (in)activation through mutagenesis, providing tools to answer a wider array of research questions across biological disciplines. Spatial and/or temporal control are granted primarily by (combinations of) specific promoters, temperature regimens, compound addition, or illumination. The use of such genetic tool kits is particularly widespread in invertebrate animal modelsbecause they can be applied to study biological processes in short time frames and on large scales, using organisms amenable to easy genetic manipulation. Recent years witnessed an exciting expansion and optimization of such tools, of which we provide a comprehensive overview and discussion regarding their use in invertebrates. The mechanism, applicability, benefits, and drawbacks of each of the systems, as well as further developments to be expected in the foreseeable future, are highlighted.

Folgering JH et al. (2008) Prog Biophys Mol Biol "Molecular basis of the mammalian pressure-sensitive ion channels: focus on vascular mechanotransduction."

Dedman A, Patel A, Delmas P, Honore E, Folgering JH, Sharif-Naeini R

[Prog Biophys Mol Biol, 2008]

Mechano-gated ion channels are implicated in a variety of neurosensory functions ranging from touch sensitivity to hearing. In the heart, rhythm disturbance subsequent to mechanical effects is also associated with the activation of stretch-sensitive ion channels. Arterial autoregulation in response to hemodynamic stimuli, a vital process required for protection against hypertension-induced injury, is similarly dependent on the activity of force-sensitive ion channels. Seminal work in prokaryotes and invertebrates, including the nematode Caenorhabditis elegans and the fruit fly drosophila, greatly helped to identify the molecular basis of volume regulation, hearing and touch sensitivity. In mammals, more recent findings have indicated that members of several structural family of ion channels, namely the transient receptor potential (TRP) channels, the amiloride-sensitive ENaC/ASIC channels and the potassium channels K(2P) and K(ir) are involved in cellular mechanotransduction. In the present review, we will focus on the molecular and functional properties of these channel subunits and will emphasize on their role in the pressure-dependent arterial myogenic constriction and the flow-mediated vasodilation.

Karn J et al. (1982) "unc-54 myosin heavy-chain gene of C. elegans: Genetics, sequence, structure."

Karn J, Barnett L, McLachlan AD

[1982]

The small soil nematode Caenorhabditis elegans is an attractive organism for the molecular study of muscle function and development because of its anatomical simplicity and suitability for genetic and biochemical analysis (Brenner 1974; Sulston and Horvitz 1977). The body-wall musculature of C. elegans is composed of 95 cell disposed in four quadrants, which run the length of the animal beneath the cuticle. The musculature is obliquely striated, and the sarcomeres are oriented parallel to the long axis of the animal. Since these cells represent a large reaction of the animal mass, isolation of contractile proteins is comparatively simple (Epstein et al. 1974; Waterston et al. 1974, 1977a; Harris and Epstein 1977; Mackenzie and Epstein 1980). Mutants affecting the characteristic pattern of motility of C. elegans can be easily identified, and microscopic examination of these "uncoordinated," or unc strains, in the living animal by polarized light microscopy or, more carefully, by electron microscopy has led to the identification of 22 genes that produce altered muscle phenotypes (Waterston et al. 1980; Zengel and Epstein 1980). Of these, two are known to code for major structural proteins of muscle: The unc-54 gene codes for the major heavy chain of myosin (Epstein et al. 1974; MacLeod et al. 1977b), whereas the un-15 gene codes for paramyosin, the core protein of the thick filaments (Waterston et al. 1974; MacLeod et al. 1977a; Harris and Epstein 1977).

Zemva J et al. (2011) Curr Diabetes Rev "Central insulin and insulin-like growth factor-1 signaling: implications for diabetes associated dementia."

Schubert M, Zemva J

[Curr Diabetes Rev, 2011]

Patients with type 2 diabetes (T2DM) have a two- to three-fold increased risk for Alzheimer's disease (AD), the most common form of dementia. Vascular complications might explain partially the increased incidence of neurodegeneration in patients with T2DM. Alternatively, neuronal resistance for insulin/insulin-like growth factor-1 (IGF- 1) might represent a molecular link between T2DM and AD, characterizing AD as "brain-type diabetes". According to this hypothesis, brains from AD patients showed substantially downregulated expression of the Insulin receptor (IR), the IGF-1 receptor (IGF-1R), and the insulin receptor substrate (IRS) proteins. Similar changes in insulin/IGF-1 signaling (IIS) have been described in animals fed a high fat diet and human T2DM, suggesting that decreased IIS might be involved in the pathogenesis of both T2DM and AD. In contrast, type 2 diabetic patients suffering from AD accumulate less -amyloid (A) compared to non-diabetic AD patients raising the question, whether the changes in IIS are cause, consequence, or compensatory counterregulation to neurodegeneration. Recent data in C. elegans showed that reducing IIS decreases A toxicity. This effect is accomplished via two transcription factors downstream of IIS, DAF-16 and HSF- 1: The first detoxification path leads to degradation of the toxic misassemblies and is mediated via HSF-1. The second mechanism mediates the formation of low toxic, high molecular weight aggregates from highly toxic small molecular weight aggregates regulated by DAF-16 suggesting that Insulin/IGF-1 transmitted signals influence A proteotoxicity. The current review discusses possible implications of recent findings in humans and model organisms for the understanding and possible therapeutic approaches of diabetes associated dementia.