Wg signaling in Drosophila heart development as a pioneering model

The heart is one of the first functional embryonic organs occurring during development. The fundamental developmental processes and genes involved in cardiogenesis are conserved between the invertebrates and vertebrates. In the past fifteen years, one of signaling pathways that has been best characterized in heart development in both invertebrates and vertebrates is the Wg/Wnt signaling pathways. Since our discovery of the Wg signaling required for the early heart development in Drosophila, the past fifteen years have witnessed tremendous progress in the understanding of specific Wnt signaling pathways in vertebrate cardiogenesis. This review will summarize the current state of knowledge of Wg signaling transduction in Drosophila heart development, which will benefit our understanding of vertebrate cardiogenesis and human congenital malformations.     

Imprinting of genes and the Barker hypothesis.

Several common adult diseases appear to be related to impaired fetal growth and this may be caused either by nutritional inadequacies at particular stages of pregnancy or by variation in alleles at specific growth loci. Little is known about the genes involved in the underlying mechanism. This review proposes that at least some of the effects have their origins at imprinted loci, genes that are unusual because they are expressed from only one parental allele. Many imprinted genes are crucial for fetal growth and determine birthweight. They can be disrupted in the early embryo by environmental influences and these disruptions can be inherited through many cell cycles into adult tissues. Their disruption can affect specific organs during fetal development and disruption could affect adult disease in a variety of direct and indirect means. Imprinted genes may be particularly vulnerable to disruption as they are functionally haploid and their expression is regulated by different means from the rest of the genome. Thus many imprinted genes provide plausible candidates for programming adult disease and warrant further study in this context.     

Maternal influences on epigenetic programming of the developing hypothalamic-pituitary-adrenal axis

Parental and environmental factors during the prenatal and postnatal periods permanently affect the physiology and metabolism of offspring, potentially increasing disease risk later in life. Underlying mechanisms are being elucidated, and effects on a number of organs and metabolic pathways are likely involved. In this review, we consider effects on the developing hypothalamic-pituitary-adrenal (HPA) axis, which may represent a common pathway for developmental programming. The focus is on prenatal and early postnatal development, during which the HPA axis may be programmed in a manner that affects health for a lifetime. Programming of the HPA axis involves, at least in part, epigenetic remodeling of chromatin, leading to alterations in the expression of genes in many organs and tissues involved in HPA activation and response, including the hippocampus and peripheral tissues. Examples of developmental epigenetic modifications affecting the HPA axis as well as target tissues are provided.     

Genetic approaches to understanding sugar-response pathways

Plants as photoautotrophic organisms are able to produce the carbohydrates they require and have developed mechanisms to co-ordinate carbohydrate production and its metabolism. Carbohydrate-derived signals regulate the expression of genes involved in both photosynthesis and metabolism, and control carbohydrate partitioning. A number of genetic approaches have been initiated to understand sugar-response pathways in plants and identify the components involved. Screening strategies to date have been based on the effects of high sugar media on early seedling development or on changes in the enzyme activity or expression of sugar-responsive genes. These screens have established roles for plant hormones in sugar-response pathways, in particular for abscisic acid. The present emphasis on the role of plant hormones in sugar responses is due to the fact that mutants could be readily identified as belonging to these established pathways, but also results from the nature of the mutant screens in use. Progress is being made on the identification of mutants and genes that may be specific to sugar-signalling pathways. It is also expected that the modification of existing screens may target sugar-signalling pathways more directly. Genetic approaches may be especially useful in identifying components of novel signalling pathways unique to plants, and their combination with genomic and molecular approaches will guide future research.     

The Genes Raw and Ribbon Are Required for Proper Shape of Tubular Epithelial Tissues in Drosophila

The products of two genes, raw and ribbon (rib), are required for the proper morphogenesis of a variety of tissues. Malpighian tubules mutant for raw or rib are wider and shorter than normal tubules, which are only two cells in circumference when they are fully formed. The mutations alter the shape of the tubules beginning early in their formation and block cell rearrangement late in development, which normally lengthens and narrows the tubes. Mutations of both genes affect a number of other tissues as well. Both genes are required for dorsal closure and retraction of the CNS during embryonic development. In addition, rib mutations block head involution, and broaden and shorten other tubular epithelia (salivary glands, tracheae, and hindgut) in much same manner as they alter the shape of the Malpighian tubules. In tissues in which the shape of cells can be observed readily, rib mutations alter cell shape, which probably causes the change in shape of the organs that are affected. In double mutants raw enhances the phenotypes of all the tissues that are affected by rib but unaffected by raw alone, indicating that raw is also active in these tissues.     

Protective effects of AMP‐activated protein kinase in the cardiovascular system

Cardiovascular diseases remain the leading cause of mortality worldwide. Recent studies of AMP-activated protein kinase (AMPK), a highly conserved sensor of cellular energy status, suggest that there might be therapeutic value in targeting the AMPK signaling pathway. AMPK is found in most mammalian tissues, including those of the cardiovascular system. As cardiovascular diseases are typically associated with blood flow occlusion and blood occlusion may induce rapid energy deficit, AMPK activation may occur during the early phase upon nutrient deprivation in cardiovascular organs. Therefore, investigation of AMPK in cardiovascular organs may help us to understand the pathophysiology of defence mechanisms in these organs. Recent studies have provided proof of concept for the idea that AMPK is protective in heart as well as in vascular endothelial and smooth muscle cells. Moreover, dysfunction of the AMPK signalling pathway is involved in the genesis and development of various cardiovascular diseases, including atherosclerosis, hypertension and stroke. The roles of AMPK in the cardiovascular system, as they are currently understood, will be presented in this review. The interaction between AMPK and other cardiovascular signalling pathways such as nitric oxide signalling is also discussed.     

Appendage regeneration in anamniotes utilizes genes active during larval-metamorphic stages that have been lost or altered in amniotes: The case for studying lizard tail regeneration

This review elaborates the idea that organ regeneration derives from specific evolutionary histories of vertebrates. Regenerative ability depends on genomic regulation of genes specific to the life-cycles that have differentially evolved in anamniotes and amniotes. In aquatic environments, where fish and amphibians live, one or multiple metamorphic transitions occur before the adult stage is reached. Each transition involves the destruction and remodeling of larval organs that are replaced with adult organs. After organ injury or loss in adult anamniotes, regeneration uses similar genes and developmental process than those operating during larval growth and metamorphosis. Therefore, the broad presence of regenerative capability across anamniotes is possible because generating new organs is included in their life history at metamorphic stages. Soft hyaluronate-rich regenerative blastemas grow in submersed or in hydrated environments, that is, essential conditions for regeneration, like during development. In adult anamniotes, the ability to regenerate different organs decreases in comparison to larval stages and becomes limited during aging. Comparisons of genes activated during metamorphosis and regeneration in anamniotes identify key genes unique to these processes, and include thyroid, wnt and non-coding RNAs developmental pathways. In the terrestrial environment, some genes or developmental pathways for metamorphic transitions were lost during amniote evolution, determining loss of regeneration. Among amniotes, the formation of soft and hydrated blastemas only occurs in lizards, a morphogenetic process that evolved favoring their survival through tail autotomy, leading to a massive although imperfect regeneration of the tail. Deciphering genes activity during lizard tail regeneration would address future attempts to recreate in other amniotes regenerative blastemas that grow into variably completed organs.     

The Myxococcus xanthus developmentally expressed asgB-dependent genes can be targets of the A signal-generating or A signal-responding pathway.

Functional Myxococcus xanthus A signal-generating and A signal-responding pathways are required for the progression through early multicellular development. To identify genes responsive to these pathways, the expression of eight early developmental genes was analyzed. This examination identified one gene as a target of the A signal-generating pathway and four genes as targets of the A signal-responding pathway.     

Derangement of growth and differentiation control in oncogenesis.

Human neoplasms develop following the progressive accumulation of genetic and epigenetic alterations to oncogenes and tumor suppressor genes. These alterations confer a growth advantage to the cancer cell, leading to its clonal proliferation, invasion into surrounding tissues, and spread to distant organs. Genes that are altered in neoplasia affect three major biologic pathways that normally regulate cell growth and tissue homeostasis: the cell cycle, apoptosis, and differentiation. While each of these pathways can be defined by a unique set of molecular events, they are not biologically separate. Rather, they function more as an integrated molecular network, and perturbations in one pathway can have profound consequences on another. Insights into what distinguishes the regulation of growth and differentiation in a normal cell versus a cancer cell have led to the development of novel anticancer therapies.     

Census of orthologous genes and self-organizing maps of biologically relevant transcriptional patterns in chickens (Gallus gallus)

The launch of large-scale chicken expressed sequence tags (EST) projects has placed the chicken in the lead for the number of EST sequences in agriculturally important animals. More than 451,000 chicken ESTs derived from over 158 libraries have been deposited in the NCBI dbEST database as of December 2003. But how many genes these ESTs represent and how they are expressed in different chicken tissues/organs remain undetermined. In the present research, we developed a human gene-based strategy for census of chicken orthologous genes and identification of their expression patterns. Among 34,157 human coding genes used in the study, BLAST analysis revealed that 11,066 genes provisionally matched 248,628 chicken ESTs. Based on the average EST abundance of the orthologous genes, the current public repository of chicken ESTs could represent 20,000 provisional genes. Analysis of gene expression in 14 single tissues/organs showed that approximately 15% of genes were expressed exclusively in single tissue/organ whereas the remaining 85% of genes were co-expressed in two or more tissues/organs. A majority (91.15%) of genes expressed in chicken embryos were also expressed at post-hatch stages, indicating that most genes activated in chicken embryos could serve housekeeping functions. Self-organizing maps (SOM) analysis organized 8807 provisional genes in selected chicken tissues into 98 clusters with each cluster being indicative of common regulatory factors and pathways. A total of 969 provisional orthologous genes were identified as preferentially expressed genes (PEGs) in various chicken tissues/organs (LOD>3.0). No doubt, the present study on gene expression patterns will provide insight into dynamics of metabolic pathways and tissue/organ programming and reprogramming in chickens.     

Longevity determined by developmental arrest genes in Caenorhabditis elegans

The antagonistic pleiotropy theory of aging proposes that aging takes place because natural selection favors genes that confer benefit early on life at the cost of deterioration later in life. This theory predicts that genes that impact development would play a key role in shaping adult lifespan. To better understand the link between development and adult lifespan, we examined the genes previously known to be essential for development. From a pool of 57 genes that cause developmental arrest after inhibition using RNA interference, we have identified 24 genes that extend lifespan in Caenorhabditis elegans when inactivated during adulthood. Many of these genes are involved in regulation of mRNA translation and mitochondrial functions. Genetic epistasis experiments indicate that the mechanisms of lifespan extension by inactivating the identified genes may be different from those of the insulin/insulin-like growth factor 1 (IGF-1) and dietary restriction pathways. Inhibition of many of these genes also results in increased stress resistance and decreased fecundity, suggesting that they may mediate the trade-offs between somatic maintenance and reproduction. We have isolated novel lifespan-extension genes, which may help understand the intrinsic link between organism development and adult lifespan.     

Isolation of early genes expressed in reproductive organs of the dioecious white campion (Silene latifolia) by subtraction cloning using an asexual mutant

The dioecious white campion (Silene latifolia) has been chosen as a working model for sexual development. In this species, sexual dimorphism is achieved through two distinct developmental blocks: inhibition of carpel development in male flowers, and early arrest of anther differentiation in female flowers. The combined advantages of the dioecious system and the availability of a sexual mutant lacking both male and female reproductive organs have been exploited in a molecular subtraction approach using male and asexual flower buds. This resulted in the cloning of 22 cDNA clones expressed in stamens at distinct stages of development. Fourteen of these clones corresponded to genes whose expression was detected in pre-meiotic stamens, a stage of development for which very little information is presently available. Furthermore, the absence of similarities with database sequences for ten clones suggests that they represent novel genes. Functional analysis of each clone will enable their positioning within the reproductive organ developmental pathway(s). In parallel, these clones are being exploited as developmental markers of early differentiation within the flower.